Epothilone derivatives

ABSTRACT

Epothilone derivatives of Formula (I) and their use as a pharmaceutical.

The present invention relates to epothilone derivatives and theirpharmaceutical use, pharmaceutical composition containing the same andmethods for their preparation.

Despite the widespread use of Taxol® and Taxotere® in the treatment ofmany different tumor types, the impact of taxanes on patient survivalhas been modest, and the over-whelming majority of metastatic solidtumors remain incurable. Taxane treatment is associated with a number ofsignificant side-effects, and the effectiveness of taxanes can beseverely limited by the rapid development of drug resistance mechanisms.In view of these limitations as well as the side-effects commonlyobserved with standard combination therapies, there is a clear need forthe identification of novel cytotoxic anti-cancer agents exhibiting animproved overall profile including spectrum of anti-tumor activity,efficacy against multi-drug resistant tumors, safety and tolerability.

The microtubule-stabilizing effect of the epothilones is first describedby Bollag et al., Cancer Research 55, 1995, 2325-33. A suitabletreatment schedule for the treatment of different types of tumors,especially tumors which are refractory to the treatment by otherchemotherapeutics, in particular TAXOL™, using an epothilone, inparticular epothilone A or B, is described in WO 99/43320. D. Su, A.Balog et al. discussed in Angew. Chem. Int. Ed. Engl. 1997, 36, pages2093 to 2096, the structure-activity relationship of the class of theepothilones. On pages 2094 of said publication, they inter aliaconcluded that a modification of the structure of the natural compoundsat the carbon atoms indicated as C1 to C8 results in a major loss ofcytotoxicity and of loss of activity in the tubulin/microtubule system.Surprisingly, it has now been found that the C3-deoxy-epothilones offormula I have beneficial pharmacological properties and can be used forthe treatment of proliferative diseases.

Hence, the present invention relates to epothilones of formula I

Wherein

R₁ is selected from

R₂ is lower alkyl or hydrogen

R₃ is OH or hydrogen;

Z is O, C or —Z— is a bond between the two binding carbon atoms;

is a single or double bond between C2 and C3;

or salts thereof;with the proviso that when R1 is a, R3 is hydrogen and that when R1 isb, Z is O or a bond, and R2 is methyl R3 is not OH.

One embodiment of the invention is a compound of formula I

Wherein

R₁ is

R₂ is lower alkyl preferably methyl

R₃ is hydrogen;

Z is O or —Z— is a bond between the two binding carbon atoms;

is a single bond;

or salts thereof.

A further embodiment of the invention is a compound of formula I

Wherein

R₁ is

R₂ is lower alkyl or hydrogen

R₃ is OH or hydrogen;

Z is O, C or —Z— is a bond between the two binding carbon atoms;

is a single or double bond;

or salts thereof;with the proviso that when R2 is methyl and Z is O or a bond R3 is notOH.

In a further embodiment the invention provides a compound selected from

-   (Z)-(7R,8S,9S,16S)-8-Hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;-   (1S,3S,10R,11S,12S,16R)-11-Hydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;-   16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-8-hydroxy-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;-   3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;-   (Z)-(7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-8-hydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;-   (1S,3S,10R,11S,12S,16R)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;-   (E)-(7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-8-hydroxy-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;-   (1S,3S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;-   16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-4,8-dihydroxy-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;-   3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;-   (E)-(4S,7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-4,8-dihydroxy-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;-   (1S,3S,7S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;-   (3E,13E)-(7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-8-hydroxy-5,5,7,9-tetramethyl-oxacyclohexadeca-3,13-diene-2,6-dione;-   (E)-(1S,3S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadec-6-ene-5,9-dione;-   3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4-oxabicyclo[14.1.0]heptadecane-5,9-dione;    and-   (1S,3S,7S,10R,11S,12S,16R)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4-oxa-bicyclo[14.1.0]heptadecane-5,9-dione.

The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either unbranched or branched withsingle or multiple branching.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like (“a” as anindefinite article or as a numeral meaning “one”).

Asymmetric carbon atoms that are optionally present in the substituentsmay exist in the (R), (S) or (R,S) configuration, preferably in the (R)or (S) configuration. Substituents on a double bond or on a ring, forexample on the carbon atoms to which Z in formula I is bonded, may bepresent in cis- (═Z—) or trans- (=E-) form. The present compounds maythus exist as mixtures of isomers or as pure isomers, preferably as purediastereoisomers. Alkyl is preferably an alkyl radical with 1 to 10carbon atoms, preferably lower alkyl, especially methyl.

Lower alkyl is unbranched or has mono- or multiple-branching and is inparticular methyl or ethyl.

Salts are primarily the pharmaceutically acceptable salts of compoundsof formula I.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of formula I with abasic nitrogen atom, especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, hydrohalic acids, such ashydrochloric acid, sulphuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulphonic or sulphamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyricacid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinicacid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid,tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids,such as glutamic acid, aspartic acid, N-methylglycine, acetylaminoaceticacid, N-acetylasparagine or N-acetylcysteine, pyruvic acid, acetoaceticacid, phosphoserine, 2- or 3-glycerophosphoric acid, maleic acid,hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid,benzoic acid, salicylic acid, 1- or 3-hydroxy-naphthyl-2-carboxylicacid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid,2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid,phenylacetic acid, glucuronic acid, galacturonic acid, methane- orethane-sulphonic acid, 2-hydroxyethanesulfonic acid,ethane-1,2-disulphonic acid, benzenesulphonic acid,2-naphthalenesulphonic acid, 1,5-naphthalenedisulphonic acid,N-cyclohexylsulphamic acid, N-methyl-, N-ethyl- or N-propyl-sulphamicacid, or other organic protonic acids, such as ascorbic acid.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. Only the pharmaceutically acceptable salts or freecompounds (if the occasion arises, in the form of pharmaceuticalpreparations) attain therapeutic use, and these are therefore preferred.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, including those salts that can beused as intermediates, for example in the purification or identificationof the novel compounds, hereinbefore and hereinafter any reference tothe free compounds is to be understood as referring also to thecorresponding salts, as appropriate and expedient.

The compounds of formula I have valuable pharmacological properties, asdescribed hereinbefore and hereinafter.

The antiproliferative activity of the compounds of formula I may beproved as follows:

Stock solutions of the test compound of formula I 10 mM) in DMSO areprepared and stored at −20° C. Human KB-31 and (multidrug-resistant,P-gp 170 overexpressing) KB-8511 epidermoid carcinoma cells are from Dr.M. Baker, Roswell Park Memorial Institute (Buffalo, N.Y., USA) (fordescription see also Akiyama et al., Somat. Cell. Mol. Genetics. 11,117-126 (1985) und Fojo A., et al., Cancer Res. 45, 3002-3007(1985)—KB-31 und KB-8511 both are derivatives of the KB-cell line(American Type Culture Collection) and are human epidermoid carcinomacells. KB-31 cells can be cultivated in mono-layers using calf serum(M.A. Bio-products), L-glutamine (Flow), penicillin (50 Units/ml) undstreptomycin (50 μg/ml (Flow); they then grow with a doubling rate ofabout 22 hours, and the relative efficiency of plating them out lies atabout 60%. KB-8511 is a variant derived from the KB-31 cell line whichhas been obtained by treatment cycles with colchicine, and it shows anabout 40-fold relative resistance against colchicin in comparison toKB-31 cells). The cells are incubated at 37° C. in an incubator with 5%v/v CO₂ and at 80% relative atmospheric humidity in MEM Alpha-mediumwhich contains ribonucleosides und desoxyribonucleosides (Gibco BRL),complemented with 10 IU Penicillin, 10 μg/ml Streptomycin and 5% fetalcalf serum. The cells are spread in an amount of 1.5×10³ cells/well in96-well-microtiter plates and incubated overnight. Serial dilutions ofthe test compounds in culture medium are added at day 1. The plates arethen incubated for an additional period of four days, after which thecells are fixed using 3.3% v/v glutaraldehyde washed with water andfinally stained with 0.05% w/v methylen blue. After washing again, thestain is eluted with 3% HCl and the optical density at 665 nm ismeasured with a SpectraMax 340 (Molecular Devices, Sunnyvale, Calif.).IC50-values are determined by mathematically fitting the data to curvesusing the SoftPro2.0 program (Molecular Devices, Sunnyvale, Calif.) andthe formula

[(OD treated)−(OD start)]/[(OD control)−(OD start)]×100.

The IC50 is defined as the concentration of a test compound at the endof the incubation period that leads to 50% of the number of cells incomparison to controls without test compound (concentration athalfmaximal inhibition of cell growth). Compounds of the formula Ipreferably show here and IC50 in the range from 0.1×10⁻⁹ to 500×10⁻⁹M,preferably between 0.1 and 80 nM.

Owing to these properties, the compounds are suitable for the treatmentof proliferative diseases, especially tumour diseases, includingmetastases; for example solid tumours such as lung tumours, breasttumours, colorectal tumours, prostate tumours, melanomas, brain tumours,pancreas tumours, neck tumours, bladder tumours, neuroblastomas, throattumours, but also proliferative diseases of blood cells, such asleukaemia; also for the treatment of other diseases which respond totreatment with microtubule depolymerisation inhibitors, such aspsoriasis.

In the following preparation processes for intermediates, functionalgroups which are to be in protected form can be protected if necessaryat suitable stages, whereby selective protection or deprotection is alsopossible. The protecting groups and the methods of introducing and/orremoving them correspond to those named above under process a),especially those named in the above-mentioned standard reference worksor, in particular, in the examples. As a rule, protecting groups are notmentioned in the following; the following examples show where the usageof the protecting groups is appropriate or necessary and can thereforebe regarded as a preferred instruction as to when protecting groupsshould be used and if compounds should be produced with other radicals.In the following, protecting groups are not mentioned at all the pointswhere they are appropriately used. The person skilled in the art isclear as to where this usage ought to or must occur.

The compounds of formula I may be prepared by deprotection of a compoundof formula II for example by treating with HF in an inert solvent suchas acetonitrile.

A compound of formula II may be prepared by ring closure of a compoundof formula III

For example by first treating with trichlorobenzoylchloride in thepresence of a base such as triethylamine and then treating with DMAPpreferably under dilute conditions.

A compound of formula III may be prepared by converting a compound offormula IV

for example by treating with LiOH in a solvent such as i-PrOH/H₂O.

A compound of formula IV may be prepared by coupling a compound offormula V

With a vinyl iodide of formula VI

for example by first performing a hydroboration on a compound of formulaV with a reagent such as 9-BBN then treating A vinyl iodide of formulaVI with the resulting product in the presence of a catalyst such asPd(dppf)₂Cl₂ and a reagent such as AsPh₃.

A compound of formula V may be prepared by treating a compound offormula VII

with NO₂-PhSeCN, BU₃P followed by hydrogen peroxide and preferably abase. A compound of formula VII may be prepared by hydrogenation of acompound of formula VIII

for example using a palladium catalyst in the presence of hydrogen.

A compound of formula VIII may be prepared by first deprotonation of acompound of formula IX for example with LDA in the presence of a basepreferably at a low temperature e.g. −78° C.

followed by treatment with an aldehyde of formula X

Compounds of formula I wherein Z is O may be prepared by first preparingthe “13-ene” derivative and epoxidating for example by treating withmethyltrioxorhenium in a solvent mixture of H₂O₂/H₂O/Pyridine.

Starting Materials

The starting materials are known, may be produced by known processes orare commercially available, or they may be produced as described in thefollowing:

A compound of formula I can be administered alone or in combination withone or more other therapeutic agents, possible combination therapytaking the form of fixed combinations or the administration of acompound of the invention and one or more other therapeutic agents beingstaggered or given independently of one another, or the combinedadministration of fixed combinations and one or more other therapeuticagents. A compound of formula I can besides or in addition beadministered for tumour therapy in combination with chemotherapy,radiotherapy, immunotherapy, surgical intervention, or a combination ofthese. Long-term therapy is equally possible as is adjuvant therapy inthe context of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumour regression, or even chemopreventive therapy, for example inpatients at risk.

Therapeutic agents for possible combination are especially one or moreantiproliferative, cytostatic or cytotoxic compounds, for example one ormore chemotherapeutic agent(s) selected from the group comprising theclassical chemotherapeutic agents, an inhibitor of polyaminebiosynthesis, an inhibitor of protein kinase, especially ofserine/threonine protein kinase, such as protein kinase C, or oftyrosine protein kinase, such as epidermal growth factor receptorprotein tyrosine kinase, a cytokine, a negative growth regulator, suchas TGF-β or IFN-β, an aromatase inhibitor, and a classical cytostatic.

Compounds according to the invention are not only for the (prophylacticand preferably therapeutic) treatment of humans, but also for thetreatment of other warm-blooded animals, for example of commerciallyuseful animals, for example rodents, such as mice, rabbits or rats, orguinea-pigs. They may also be used as a reference standard in the testsystems described above to permit a comparison with other compounds.

A compound of formula I may also be used for diagnostic purposes, forexample with tumours that have been obtained from warm-blooded animal“hosts”, especially humans, and implanted into mice to test them fordecreases in growth after treatment with such a compound, in order toinvestigate their sensitivity to the said compound and thus to improvethe detection and determination of possible therapeutic methods forneoplastic diseases in the original host.

Within the groups of preferred compounds of formula I mentionedhereinafter, definitions of substituents from the general definitionsmentioned hereinbefore may reasonably be used, for example, to replacemore general definitions with more specific definitions or especiallywith definitions characterized as being preferred; the definitionscharacterised as being preferred, or exemplary (“e.g.”, “such as”, “forexample”), are preferred.

The following examples illustrate the invention, but are not intended torestrict their scope in any way.

Temperatures are measured in degrees celsius. Unless otherwiseindicated, the reactions take place at room temperature.

Table of Abbreviations

HF Hydrofluoric acid

9-BBN 9-borabicyclo-nonane

AcOEt Ethyl acetate

AcOH Acetic acid

AsPh₃ Triphenylarsine

Bu₃P Tributyl phosphine

Bu₄N(HSO₄) Tetrabutylammonium hydrogen sulfate

BuLi Butyl lithium

CH₂Cl₂ Dichloromethane

CH₂I₂ Methylene iodide

CH₃CN Acetonitrile

CHI₃ Iodoform

CrCl₂ Chromium chloride

CrCl₂ Chrome chloride

CSA (+)-Camphor-10-sulfonic acid

CsCO₃ Cesium carbonate

DIAD Diisopropyl-azodicarboxylate

DMAP Dimethylaminopyridine

DMF Dimethylformamide

DMM Dimethoxymethane

Et₂O Diethyl ether

Et₂Zn Diethyl zinc

H₂O water

H₂O₂ Hydrogen peroxide

Hex Hexane

i-Pr₂NH Diisopropyl amine

i-PrOH isopropanol

K₂CO₃ Potassium carbonate

KHSO₄ Potassium hydrogenosulfate

LiOH Lithium hydroxide

MeOH Methanol

MgSO₄ Magnesium sulfate

MTO Methyltrioxorhenium

Na₂B₄O₇.10H₂O Sodium tetraborat-decahydrat

Na₂EDTA Ethylenediaminetetraacetic acid disodium salt

Na₂SO₄ Sodium sulfate

NaHCO₃ Sodium bicarbonate

NH₄Cl Ammonium chloride

Pd(dppf)₂Cl₂ 1,1-Bis(diphenylphosphino) ferrocene palladium chloride

Pd/C Palladium on charcoal

Ph₃P triphenylphosphine

Rf Retention to front

TBAF Tetra butylammonium fluoride

TBSOTf t-Butyldimethylsilyl trifluoromethanesulfonate

TESCl Triethylsilyl chloride

TESOTf Triethylsilyl trifluoromethanesulfonate

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

EXPERIMENTAL PART Example 1(Z)-(7R,8S,9S,16S)-8-Hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione(14)

To a solution of 13 (50 mg, 0.085 mmol) in 3 mL CH₃CN and in a Teflontube is added at rt 0.6 mL of HF.Pyridine (70/30) and the reactionmixture is stirred for 2 h at rt. The reaction mixture is washed with a5% solution of NaHCO₃, extracted 3 times with 10 mL AcOEt and then theorganic layers are dried (MgSO₄). Purification by flash columnchromatography (F-lexane/Et₂O—90/10 to 50/50) afforded 14 as acolourless oil.

ESI-MS: M(C₂₇H₄₁NO₄S)=475.7, (M+H)⁺=476.1.

Rf: Hexane/Acetone—50/50:0.61.

¹H NMR (400 MHz, CDCl₃): δ=7.00 (s, 1H, NC═CHS), 6.60 (s, 1H), 5.25 (m,1H), 5.15 (m, 1H), 3.70 (m, 1H), 3.20 (m, 1H), 2.90 (s, 3H), 2.60 (m,2H), 2.30 (m, 2H), 2.10 (m, 2H), 2.05 (s, 3H), 1.95 (m, 1H), 1.60 (s,3H), 1.30 (s, 6H), 1.20 (d, 3H), 1.00 (d, 3H).

(1a)—Compound 2

To a solution of Phosphonoacetate (10.2 g, 0.048 mmol) in 50 mL THF,under argon at 0° C., is added dropwise a 1.6M solution of n-BuLi (30.5mL, 0.048 mmol) and the reaction mixture is stirred at 0° C. over 30min. The solution is cooled to −78° C. and aldehyde 1 (5 g, 0.039 mmol)in 10 mL THF is added dropwise in 10 min. The reaction mixture isstirred at rt for 2 h and quenched with a saturated solution of NH₄Cl,extracted 3 times with 20 mL Et₂O. The combined organic layers are dried(MgSO₄) and concentrated in vacuum. Purification by flash columnchromatography (Hexane/Et₂O—90/10) afforded 2 as an oil.

ESI-MS: M(C₁₀H₁₆O₃)=184.2, (M+H₂O)⁺=202.0.

Rf: Hexane/Acetone—50/50:0.68.

¹H NMR (400 MHz, CDCl₃): δ=7.00 (d, 1H), 5.85 (d, 1H), 3.75 (s, 3H),2.45 (q, 2H), 1.25 (s, 6H), 1.00 (t, 3H).

(1b)—Compound 4

To a solution of i-Pr₂NH (0.135 mL, 0.969 mmol) in 2.5 mL THF at 0° C.is added dropwise over 10 min a 1.6M solution of n-BuLi (0.6 mL, 0.969mmol). The mixture is stirred at 0° C. for 30 min and then is cooled to−78° C. for addition dropwise over 20 min of 2 (0.18 g, 0.969 mmol) in 2mL THF. After 1 h, aldehyde 3 is added (0.1 g, 0.484 mmol) in 2 mL THFand the reaction mixture is stirred for another 1 h at −78° C. and thenis quenched with a saturated solution of NH₄Cl, extracted 3 times with10 mL CH₂Cl₂. The combined organic layers are dried (MgSO₄) andconcentrated in vacuum. Purification by flash column chromatography(Hexane/Acetone—90/10) afforded 4 in a 2.5/1 ratio.

R^(f): Hexane/Acetone—50/50:0.70.

¹H NMR (400 MHz, CDCl₃): δ=7.30 (m, 5H), 7.00 (d, 1H), 5.95 (d, 1H),4.50 (s, 2H), 3.75 (s, 3H), 3.45 (m, 2H), 3.35 (m, 1H), 3.15 (m, 1H),1.75 (m, 2H), 1.55 (m, 2H), 1.30 (s, 6H), 1.05 (d, 3H), 0.80 (d, 3H).

ESI-MS: M(C₂₃H₃₄O₅)=390.5, (M+H)⁺=391.2.

(1c)—Compound 5

To a solution of 4 (0.4 g, 1.024 mmol) in 5 mL CH₂Cl₂ at 0° C. is addeddropwise 2,6-lutidine (0.24 mL, 2.048 mmol) followed by TBSOTf (0.35 mL,1.536 mmol). The mixture is stirred at 0° C. for 2 h and then isquenched with a saturated solution of NH₄Cl, extracted 3 times with 25mL CH₂Cl₂. The combined organic layers are dried (MgSO₄) andconcentrated in vacuum. Purification by flash column chromatography(Hexane/Et₂O—90/10) afforded 5 as an oil.

ESI-MS: M(C₂₉H₄₈O₅Si)=504.8, (M+H₂O)⁺=522.1.

R^(f): Hexane/Acetone—50/50:0.80.

¹H NMR (400 MHz, CDCl₃): δ=7.30 (m, 5H), 7.10 (d, 1H), 5.90 (d, 1H),4.50 (s, 2H), 3.82 (m, 1H), 3.75 (s, 3H), 3.40 (m, 2H), 3.05 (m, 1H),1.70 (m, 2H), 1.40 (m, 2H), 1.30 (2s, 6H), 1.05 (d, 3H), 0.92 (d, 3H)0.89 (s, 9H), 0.05 (s, 6H).

(1d)—Compound 6

To a solution of 5 (0.45 g, 0.89 mmol) in 10 mL MeOH at rt is added Pd/C(0.1 g, 10%) and the reaction mixture is stirred under a 5 bar pressureof H₂ for 6 h. The mixture is filtered on hyflo and purification byflash column chromatography (Hexane/Et₂O—80/20 to 50/50) afforded 6 as acolourless oil.

ESI-MS: M(C₂₂H₄₄O₅Si)=416.7, (M+H)⁺=417.2.

R^(f): Hexane/Acetone—50/50:0.70.

¹H NMR (400 MHz, CDCl₃): S=3.80 (m, 1H), 3.75 (s, 3H), 3.60 (m, 2H),3.15 (m, 1H), 2.20 (m, 2H), 1.80 (m, 2H), 1.40-1.70 (m, 4H), 1.15 (2s,6H), 1.05 (d, 3H), 0.92 (d, 3H) 0.89 (s, 9H), 0.05 (s, 6H).

(1e)—Compound 7

To a solution of 6 (0.35 g, 0.84 mmol) in 10 mL THF at rt is addedNO₂-PhSeCN (1.16 g, 4.2 mmol) followed by Bu₃P (1 mL, 4.2 mmol). Thereaction mixture is stirred at rt for 2 h before the addition of NaHCO₃(2.11 g, 25.2 mmol) and a 30% solution of H₂O₂ (2.6 mL, 25.2 mmol). Thesolution is stirred for 2 h at rt and then is quenched with a saturatedsolution of NH₄Cl, extracted 3 times with 10 mL CH₂Cl₂. The combinedorganic layers are dried (MgSO₄) and concentrated in vacuum.Purification by flash column chromatography (CH₂Cl₂—100 thenHexane/Et₂O—90/10 to 50/50) afforded 7 as colourless oil.

ESI-MS: M(C₂₂H₄₂O₄Si)=398.7, (M+H)⁺=399.2.

Rf: Hexane/Acetone—70/30:0.61.

¹H NMR (400 MHz, CDCl₃): δ=5.70 (m, 1H), 5.00 (m, 2H), 3.80 (m, 1H),3.75 (s, 3H), 3.20 (m, 1H), 2.20 (m, 2H), 1.85 (m, 2H), 1.40 (m, 2H),1.20 (s, 3H), 1.15 (s, 3H), 1.05 (d, 3H), 0.92 (d, 3H), 0.89 (s, 9H),0.05 (s, 6H).

(1f)—Compound 11

To a 0.5M solution of 9-BBN in 2 mL THF (2.3 mL, 1.154 mmol) is addeddropwise 7 (0.23 g, 0.577 mmol) in 2 mL THF at rt. After 2 h TLCanalysis revealed the complete consumption of the starting olefin. In aseparate flask, containing vinyl iodide 10 (0.27 g, 0.577 mmol) in 2 mLDMF were added successively, CsCO₃ (0.37 g, 1.15 mmol), AsPh₃ (35 mg,0.115 mmol), Pd(dppf)₂Cl₂ (85 mg, 0.115 mmol) and H₂O (0.31 mL, 17.3mmol). In first solution is added H₂O (0.11 mL, 5.8 mmol) to quench theexcess 9-BBN and the alkyl borane solution is added rapidly by syringeto the solution containing the vinyl iodide. The reaction mixture isstirred at rt overnight and quenched with H₂O, extracted 3 times with 20mL Et₂O. The combined organic layers are dried (MgSO₄) and concentratedin vacuum. Purification by flash column chromatography(Hexane/Et₂O—90/10 to 50/50) afforded 11 as a colourless oil.

ESI-MS: M(C₄₀H₇₃NO₅Si₂S)=736.3, (M+H)⁺=737.1.

Rf: Hexane/Acetone—70/30:0.58.

¹H NMR (400 MHz, CDCl₃): δ=6.90 (s, 1H), 6.45 (s, 1H), 5.10 (m, 1H),4.07 (t, 1H), 3.80 (m, 1H), 3.75 (s, 3H), 3.10 (m, 1H), 2.70 (s, 3H),2.40 (m, 2H), 2.20 (m, 2H, CH₂CH₂CO₂Me), 1.99 (s, 3H), 1.90 (m, 2H),1.65 (s, 3H), 1.50 (m, 2H), 1.20 (s, 3H), 1.10 (s, 3H), 1.05 (d, 3H),0.95 (d, 3H), 0.92 (t, 9H), 0.89 (s, 9H), 0.57 (q, 6H), 0.05 (s, 6H).

(1g)—Compound 12

To a solution of 11 (0.22 g, 0.3 mmol) in 9 mL i-PrOH/H₂O—4/1 is addedLiOH (43 mg, 1.8 mmol) and the mixture is heated at 60° C. and stirredovernight. After cooling to rt, the solution is quenched with asaturated solution of NH₄Cl, extracted twice with 10 mL CH₂Cl₂ and twicewith 10 mL AcOEt. The combined organic layers are dried (MgSO₄) andconcentrated in vacuum. The crude reaction mixture is used directly inthe next step.

ESI-MS: M(C₃₃H₅₇NO₅SiS)=607.9, (M+H)⁺=608.1.

Rf: Hexane/Acetone—70/30:0.25.

¹H NMR (400 MHz, CDCl₃): δ=6.90 (s, 1H), 6.45 (s, 1H), 5.15 (m, 1H),4.07 (q, 1H), 3.80 (m, 1H), 3.20 (m, 1H), 2.70 (s, 3H), 2.30 (m, 2H),2.10 (m, 2H), 1.99 (s, 3H), 1.90 (m, 2H), 1.70 (s, 3H), 1.40 (m, 2H),1.20 (s, 3H), 1.10 (s, 3H), 1.05 (d, 3H), 0.95 (d, 3H), 0.89 (s, 9H),0.05 (s, 3H), 0.03 (s, 3H).

(1 h)—Compound 13(Z)-(7R,8S,9S,16S)-8-(tert-Butyl-dimethyl-silanyloxy)-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione

To a solution of 12 (190 mg, 0.312 mmol) in 8 mL THF at 0° C. is addedtriethylamine (0.26 mL, 1.87 mmol) followed by trichlorobenzoylchloride(0.24 mL, 1.56 mmol). After stirring for 20 min at rt, the solution isdiluted with 15 mL dry toluene and the resulting solution is addedslowly in 2 h to a previously prepared solution of DMAP (0.38 mg, 3.12mmol) in 200 mL toluene. The reaction mixture is stirred at it for 30min and then concentrated in vacuum. The crude product is purified byflash column chromatography (Hexane/Et₂O—70/30) to afford 13 as an oil.

ESI-MS: M(C₃₃H₅₅NO₄SiS)=589.9, (M+H)⁺=590.1.

Rf: Hexane/Acetone—50/50:0.74.

¹H NMR (400 MHz, CDCl₃) for major compound: δ=6.90 (s, 1H), 6.45 (s,1H), 5.25 (m, 1H), 5.10 (m, 1H), 3.80 (m, 1H), 3.10 (m, 1H), 2.70 (s,3H), 2.30 (m, 2H), 2.10 (m, 2H), 2.05 (s, 3H), 1.80 (m, 2H, CH₂CH₂CO₂),1.60 (s, 3H), 1.30 (m, 2H), 1.20 (s, 6H), 1.10 (d, 3H), 1.00 (d, 3H),0.89 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H).

Example 2(1S,3S,10R,11S,12S,16R)-11-Hydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione(15)

To a solution of 14 (8 mg, 0.017 mmol) in 0.8 mL of CH₂Cl₂ at rt isadded a 300 μL of a solution H₂O₂/H₂O/Pyridine—16/140/1 and MTO (2 mg,0.0084 mmole). The reaction mixture is stirred at rt for 1 h30 and thenis quenched with a saturated solution of NH₄Cl and extracted twice with10 mL CH₂Cl₂. The combined organic layers are dried (MgSO₄) andconcentrated in vacuum. Purification by flash column chromatography(Hexane/Acetone—90/10 to 70/30) afforded 15 in a 9/1 ratio in favour ofdesired epoxide.

ESI-MS: M(C₂₇H₄₁NO₄S)=491.7, (M+H)⁺=492.2.

Rf: Hexane/Acetone—50/50:0.52.

¹H NMR (400 MHz, CD₃OD): δ=7.20 (s, 1H, NC═CHS), 6.80 (s, 1H), 5.40 (m,1H), 3.60 (m, 1H), 3.20 (m, 1H), 2.95 (m, 1H, CH—O), 2.70 (s, 3H,CH₃CN), 2.40 (m, 2H, CH₂CH—O), 2.20 (m, 2H), 2.05 (s, 3H), 1.95 (m, 2H),1.60 (s, 3H), 1.30 (s, 6H), 1.20 (d, 3H), 1.00 (d, 3H).

Example 316-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-8-hydroxy-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione(Compound 22)

To a 50 ml plastic tube, equipped with a magnetic stir bar, aresuccessively added 21 (339 mg), 20 ml of acetonitrile and 20 ml oftetrahydrofuran. To this solution is rapidly added HF-Pyridine complex(7 ml). The reaction is monitored by TLC (CH₂Cl₂/MeOH: 95/5) and themixture is stirred at room temperature for 3 h. The reaction mixture isthen carefully added dropwise to an Erlenmeyer containing CH₂Cl₂ (100ml), distilled water (100 ml) and sodium bicarbonate (30 g). The twolayers are separated by decantation and the aqueous phase is extractedthree times with CH₂Cl₂ (100 ml). After drying with magnesium sulfate,the solvents are removed under vacuo and the crude mixture is purifiedby flash chromatography (CH₂Cl₂/MeOH:98/2 to 97/3) to finally give 22 asa white solid.

ESI-MS: 468.9 (M+H)⁺.

HPLC: Rt=7.58 min.

Rf=0.54 (Hex/acetone:30/70).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.71 (s, 1H), 7.27 (m, 2H), 6.00 (dd, 3.7Hz, 1H), 5.48 (m, 2H), 3.76 (s, 3H), 3.74 (m, 1H), 3.19 (qd, 3.7 Hz,1H), 2.97-2.84 (m, 2H), 2.64 (s, 3H), 2.45-2.01 (m, 6H), 1.81-1.64 (m,4H), 1.49-1.16 (m, 3H), 1.30 (s, 3H), 1.21 (d, 7 Hz, 3H), 1.06 (d, 7 Hz,3H), 1.02 (s, 3H).

(3a)—Compound 17

Sodium bis(trimethylsilyl) amide (18.0 ml of a 1M THF solution) isslowly added at room temperature to a suspension of the finely crushediodomethyl-triphenylphosphonium iodide (9.9 g) in 50 ml THF. Thesolution becomes quickly orange. After the end of the addition (˜15min), the mixture is cooled down to −78° C. and the aldehyde 16 (4.98 g)in THF (20 ml) is added drop wise. After 30 min stirring at −78° C., thereaction is quenched by the addition of a saturated solution of ammoniumchloride (50 ml) under vigorous stirring. The mixture is then allowed towarm up to room temperature and CH₂Cl₂ is added (100 ml). The two layersare separated by decantation and the aqueous phase is extracted twicewith CH₂Cl₂ (50 ml). After drying of the joined organic phases withsodium sulfate and evaporation of the solvents under vacuo, the residueis taken in hexane (50 ml) in order to precipitate thetriphenylphosphine oxide. The precipitate is filtered off and washedwith hexane (5 ml) and the solvent of the filtrate is removed undervacuo. This procedure is repeated twice until no more phosphine oxide ispresent in hexane solution (controlled by TLC). The crude is thenpurified by Flash chromatography (Hexane/acetone:90/10 to 60/40) toyield 17, as a clear oil which solidifies within two weeks at 4° C.

ESI-MS: 456.9 (M÷H)⁺.

Rf=0.54 (CH₂Cl₂/MeOH:90/10).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.63 (bs, 1H), 7.23 (m, 2H), 6.22 (m, 2H),4.90 (false triplet, 1H), 3.72 (s, 3H), 2.65-2.46 (m, 2H), 2.61 (s, 3H),0.88 (s, 9H), 0.04 (s, 3H), −0.14 (s, 3H).

(3b)—Compound 18

Camphorsulfonic acid (6.5 g, 28 mmol) is added carefully (˜10installments) in a solution of 17 (3.19 g, 7 mmol) in methylene chloride(150 ml) and methanol (150 ml) at 0° C. The mixture is then allowed towarm up to room temperature and is stirred for 17 h. The mixture is thencarefully poured in an Erlenmeyer containing distilled water (500 ml)and sodium bicarbonate (4.7 g) under vigorous stirring. The layers areseparated and the aqueous phase is extracted three times with CH₂Cl₂(150 ml). The organic phases are joined, dried over sodium sulfate andthe solvents are removed under vacuo. The crude, a yellow solid (2.4 g)is purified by three successive recrystallization(Hexane/CH₂Cl₂/MeOH:50/50/1) in order to give 18, a slight yellow solid.

ESI-MS: 343.0 (M+H)⁺.

Rf=0.35 (CH₂Cl₂/MeOH:90/10).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.66 (s, 1H), 7.29 (m, 2H), 6.29 (m, 2H),4.97 (m, 1H), 3.75 (s, 3H), 2.78-2.62 (m, 2H), 2.62 (s, 3H).

(3c)—Compound 19

Flask A: To a solution of 7 (1.0 g) in 15 ml THF is added 9-BBN (10 mlof a 0.5M solution in THF) drop wise at 0° C. After the end of theaddition, the ice bath is removed and the reaction mixture is allowed towarm up to room temperature. The reaction is monitored by TLC and iscomplete after 100 minutes. The excess of 9-BBN is quenched by additionof 200 μl of distilled water.

Flask B: In a 100 ml three-necked round bottomed flask, are successivelyadded the vinyl iodide TI-35 (684 mg) and 25 ml of DMF. The solution iscooled down to 0° C. and Cesium carbonate (1.36 g), Triphenylarsine (122mg), the Palladium catalyst (340 mg) and distilled water (1 ml) aresuccessively added. The content of Flask A is then rapidly added (30sec) under vigorous stirring. After 10 minutes at 0° C., the ice bath isremoved and the reaction mixture is allowed to warm up to roomtemperature. The reaction is monitored by MS and is complete after 1h15.The mixture is then poured in a 1 L Erlenmeyer containing 300 ml ofdiethyl ether and 300 ml of distilled water. The two layers areseparated by decantation and the aqueous phase is extracted twice with200 ml of diethyl ether. The organic phases are joined and dried withmagnesium sulfate. Evaporation of the solvents under vacuo yielded abrown oil (4.0 g) which is purified by flash chromatography(Hexanes/Acetone:70/30 to 30/70) to finally yield 19 as a thick yellowoil.

ESI-MS: 615.2 (M+H)⁺.

Rf=0.24 (Hex/acetone:50/50).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.58 (s, 1H), 7.21 (m, 2H), 5.50-5.27 (m,2H), 4.76 (dd, 1H), 3.74 (dd, 1H), 3.66 (s, 3H), 3.59 (s, 3H), 3.08 (m,1H), 2.63-2.31 (m, 2H), 2.54 (s, 3H), 2.16 (m, 2H), 1.96 (m, 2H), 1.77(m, 4H), 1.34-0.94 (m, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.98 (d, 3H),0.84 (s, 9H), 0.81 (d, 3H), 0.01 (s, 6H).

(3d)—Compound 20

Lithium hydroxide (163 mg) is added to a solution of 19 (700 mg) in amixture of isopropanol (16 ml) and water (4 ml). The reaction mixture isthen warmed up to 60° C. and stirred for 45 min. The mixture is thenpoured into an Erlenmeyer containing 40 ml of CH₂Cl₂ and 40 ml of water.The mixture is then acidified to pH 5 by a slow addition of Hydrochloricacid 1M under vigorous stirring (approx 6.5 ml). The two layers areseparated by decantation and the aqueous phase is extracted three timeswith 20 ml of CH₂Cl₂. The organic phases are joined and after dryingwith magnesium sulfate, removing of the solvents under vacuo, the crudeis purified by flash chromatography (CH₂Cl₂/Methanol: 95/5 to 90/10) toyield 20 as a white foam.

ESI-MS: 601.0 (M+H)⁺.

Rf=0.43 (CH₂Cl₂/MeOH:90/10).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.88 (s, 1H), 7.31 (AB system, 2H), 5.62(m, 1H), 5.47 (m, 1H), 4.84 (dd, 9.5 Hz, 1H), 3.88 (dd, 6.3 Hz, 1H),3.75 (s, 3H), 3.24 (m, 1H), 2.72-1.88 (m, 8H), 2.65 (s, 3H), 1.54-1.06(m, 5H), 1.23 (s, 3H), 1.20 (s, 3H), 1.13 (d, 7 Hz, 3H), 0.95 (d, 3H),0.94 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H).

(3e)—Compound 21

Flask A: To a solution of 20 (473 mg) and Triethylamine (770 μl) intetrahydrofuran (20 ml) at 0° C., is rapidly added2,4,6-trichlorobenzoyl chloride (740 μl). After stirring at 0° C. for 15min, the mixture is allowed to warm up to room temperature and stirredfor another 15 minutes.

Flask B: The content of Flask A is slowly added (2 h) to a solution ofDMAP (1.15 g) in 600 ml of toluene, under vigorous stirring. After theend of the addition, the mixture is stirred for an additional 30minutes. The solvents are then removed under vacuo and the residue ispurified by flash chromatography (Hexanes/acetone 60/40 to 40/60) toyield 21, as a white foam.

ESI-MS: 583.2 (M+H)⁺.

Rf=0.31 (Hex/acetone:50/50).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.59 (s, 1H), 7.16 (m, 2H), 5.89 (dd, 1H),5.37 (m, 2H), 3.72 (m, 1H), 3.64 (s, 3H), 3.05 (m, 1H), 2.74 (m, 1H),2.52 (s, 3H), 2.35 (m, 1H), 2.26-1.63 (m, 6H), 1.42-0.74 (m, 2H), 1.20(s, 3H), 1.02 (d, 7 Hz, 3H), 0.92 (s, 3H), 0.87 (d, 7 Hz, 3H), 0.84 (s,9H), 0.05 (s, 3H), 0.0 (s, 3H).

Example 43-(1,2-Dimethyl-1H-benzoimidazol-5-yl-11-hydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione(compound 23)

In a 10 ml round bottomed flask are successively introduced distilledwater (7 ml), Pyridine (50 μl) and hydrogen peroxide 30% (700 μl). Apart of this solution (5 ml) is rapidly added in a solution of 22 (94mg) in 5 ml of CH₂Cl₂ and under vigorous stirring, MTO (20 mg) is addedin one portion. After 5 h of stirring, the reaction mixture is quenchedby addition of 5 ml of a saturated aqueous NaHCO3 solution. The twolayers are separated by decantation and the aqueous phase is extractedtwice with CH₂Cl₂ (20 ml). After drying with magnesium sulfate andremoval of the solvent in vacuo, the crude mixture (a 2:1 diastereomericmixture) is purified by preparative TLC, to finally yield the purediastereomer 23, as a white powder.

ESI-MS: 485.3 (M+H)⁺.

Rf=0.40 (Hexane/acetone:30/70).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.68 (s, 1H), 7.29 (m, 2H), 6.05 (dd, 10Hz, 3 Hz, 1H), 3.81 (m, 1H), 3.76 (s, 3H), 3.27 (m, 1H), 3.12 (m, 1H),2.98 (m, 1H), 2.64 (s, 3H), 2.37-1.35 (m, 13H), 1.30 (s, 3H), 1.22 (d, 7Hz, 3H), 1.10 (d, 7 Hz, 3H), 1.03 (s, 3H).

Example 5(Z)-(7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-8-hydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione(29)

To a solution of 28 (100 mg, 0.167 mmol) in 5 mL CH₃CN and in a Teflontube is added at rt 1 mL of HF.Pyridine (70/30) and the reaction mixtureis stirred for 3 h at rt. The reaction mixture is washed with a 5%solution of NaHCO₃, extracted 3 times with 10 mL AcOEt and then theorganic layers are dried (MgSO₄). Purification by flash columnchromatography (Hexane/Acetone—90/10 to 50/50) afforded 29.

ESI-MS: M(C₂₉H₄₂N₂O₄)=482.6, (M+H)⁺=483.3.

Rf: Hexane/Acetone—30/70:0.36.

¹H NMR (400 MHz, CDCl₃): δ=7.62 (s, 1H), 7.20 (m, 2H), 5.87 (m, 1H),5.20 (m, 1H), 3.72 (m, 1H), 3.72 (s, 3H), 3.21 (m, 1H), 2.92 (m, 2H),2.60 (s, 3H), 2.30 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.63 (s, 3H),1.30 (m, 2H), 1.22 (s, 3H), 1.18 (d, 3H), 1.04 (d, 3H), 0.98 (s, 3H).

(5a)—Compound 25

To a 0.5M solution of 9-BBN in 3 mL THF (3.85 mL, 1.913 mmol) is addeddropwise 7 (0.38 g, 0.96 mmol) in 3 mL THF at rt. After 30 min TLCanalysis revealed the complete consumption of the starting olefin. In aseparate flask, containing vinyl iodide 24 (0.45 g, 0.96 mmol) in 4 mLDMF were added successively, CsCO₃ (0.62 g, 1.91 mmol), AsPh₃ (59 mg,0.19 mmol), Pd(dppf)₂Cl₂ (140 mg, 0.19 mmol) and H₂O (0.51 mL, 28.7mmol). In first solution is added H₂O (0.17 mL, 9.5 mmol) to quench theexcess 9-BBN and the alkyl borane solution is added rapidly by syringeto the solution containing the vinyl iodide. The reaction mixture isstirred at rt for 2 h and quenched with H₂O, extracted 3 times with 25mL Et₂O. The combined organic layers are dried (MgSO₄) and concentratedin vacuum. Purification by flash column chromatography(Hexane/Acetone—90/10 to 70/30) afforded 25 as an oil.

ESI-MS: M(C₄₂H₇₄N₂O₅Si₂)=743.2, (M+H)⁺=743.4.

Rf: Hexane/Acetone—50/50:0.54.

¹H NMR (400 MHz, CDCl₃): S=7.60 (s, 1H), 7.22 (m, 2H), 5.20 (m, 1H),4.75 (t, 1H), 3.80 (m, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.18 (m, 1H),2.60 (s, 3H), 2.40 (m, 2H), 2.22 (m, 2H), 1.90 (m, 2H), 1.80 (m, 2H),1.65 (s, 3H), 1.30 (m, 2H), 1.20 (s, 3H), 1.10 (s, 3H), 1.05 (d, 3H),0.93 (s, 9H), 0.92 (d, 3H), 0.91 (s, 9H), 0.09 (s, 6H), 0.03 (s, 3H),−0.14 (s, 3H).

(5b)—Compound 26

To a solution of 25 (0.5 g, 0.67 mmol) in 20 mL i-PrOH/H₂O —4/1 is addedLiOH (97 mg, 4 mmol) and the mixture is heated at 60° C. for 3 h. Aftercooling to rt, the solution is quenched with a saturated solution ofNH₄Cl, extracted 3 times with 25 mL CH₂Cl₂. The combined organic layersare dried (MgSO₄) and concentrated in vacuum. The crude product is useddirectly in the next step.

ESI-MS: M(C₄₁H₇₂N₂O₅Si₂)=729.2, (M+H)⁺=729.3.

Rf: Hexane/Acetone—30/70:0.57.

¹H NMR (400 MHz, CD₃OD): δ=7.50 (s, 1H), 7.38 (d, 1H), 7.21 (d, 1H),5.20 (m, 1H), 4.78 (t, 1H), 3.78 (m, 1H), 3.78 (s, 3H), 3.20 (m, 1H),2.60 (s, 3H), 2.40 (m, 2H), 2.08 (m, 2H), 1.93 (m, 2H), 1.80 (m, 2H),1.62 (s, 3H), 1.30 (m, 4H), 1.18 (s, 3H), 1.16 (s, 3H), 1.05 (d, 3H),0.92 (s, 9H), 0.92 (d, 3H), 0.91 (s, 9H), 0.06 (s, 6H), 0.05 (s, 3H),−0.17 (s, 3H).

(5c)—Compound 27

To a solution of 26 (0.44 g, 0.6 mmol) in 5 mL THF at rt is added a 1Msolution of TBAF (1.8 mL, 1.8 mmol) and reaction mixture is stirred atrt overnight. The reaction mixture is washed with a saturated solutionof NH₄Cl, extracted 3 times with 10 mL CH₂Cl₂ and then the organiclayers are dried (MgSO₄). Purification by flash column chromatography(Hexane/Et₂O —90/10 to 50/50) afforded 27 as a colourless oil.

ESI-MS: M(C₃₅H₅₈N₂O₅Si)=614.9, (M+H)⁺=615.3.

Rf: Hexane/Acetone—30/70:0.24.

¹H NMR (400 MHz, CD₃OD): δ=7.52 (s, 1H), 7.39 (d, 1H), 7.26 (d, 1H),5.18 (m, 1H), 4.69 (t, 1H), 3.78 (m, 1H), 3.76 (s, 3H), 3.20 (m, 1H),2.60 (s, 3H), 2.48 (m, 2H), 2.12 (m, 2H), 1.94 (m, 2H), 1.78 (m, 2H),1.62 (s, 3H), 1.30 (m, 4H), 1.15 (s, 3H), 1.06 (s, 3H), 1.05 (d, 3H),0.89 (s, 9H), 0.89 (d, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

(5d)—Compound 28(Z)-(7R,8S,9S,16S)-8-(tert-Butyl-dimethyl-silanyloxy)-16-(1,2-dimethyl-1H-benzoimidazol-5-yl)-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione

To a solution of 27 (120 mg, 0.195 mmol) in 5 mL THF at 0° C. is addedtriethylamine (0.163 mL, 1.17 mmol) followed by trichlorobenzoylchloride(0.152 mL, 0.975 mmol). After stirring for 20 min at rt, the solution isdiluted with 20 mL dry toluene and the resulting solution is addedslowly in 1 h to a previously prepared solution of DMAP (0.24 g, 1.95mmol) in 150 mL toluene. The reaction mixture is stirred at rt for 30min and then concentrated in vacuum. The crude product is purified byflash column chromatography (Hexane/Acetone—90/10 to 70/30) to afford 28as an oil.

ESI-MS: M(C₃₅H₅₆N₂O₄Si)=596.9, (M+H)⁺=597.3.

Rf: Hexane/Acetone—70/30:0.18.

¹H NMR (400 MHz, CDCl₃) for major compound: δ=7.62 (s, 1H), 7.20 (m,2H), 5.90 (m, 1H), 5.18 (m, 1H), 3.79 (m, 1H), 3.70 (s, 3H), 3.17 (m,1H), 2.60 (s, 3H), 2.30 (m, 2H), 2.10 (m, 2H), 1.80 (m, 2H), 1.63 (s,3H), 1.30 (m, 2H), 1.23 (s, 3H), 1.08 (d, 3H), 1.00 (s, 3H), 0.95 (d,3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H).

Example 6(1S,3S,10R,11S,12S,16R)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione(30)

To a solution of 29 (30 mg, 0.062 mmol) in 2 mL of CH₂Cl₂ at it is added1 mL of a solution H₂O₂/H₂O/Pyridine—16/140/1 and MTO (7.8 mg, 0.031mmole). The reaction mixture is stirred at rt for 30 min and then isquenched with a saturated solution of NH₄Cl and extracted 3 times with10 mL CH₂Cl₂. The combined organic layers are dried (MgSO₄) andconcentrated in vacuum. Purification by flash column chromatography(Hexane/Acetone—90/10 to 70/30) afforded 30 in more than 10/1 ratio infavour of desired epoxide.

ESI-MS: M(C₂₉H₄₂N₂O₅)=498.6, (M+H)⁺=498.9.

Rf: Hexane/Acetone—30/70:0.25.

¹H NMR (400 MHz, CDCl₃): δ=7.62 (s, 1H), 7.21 (m, 2H), 6.00 (m, 1H),3.78 (m, 1H), 3.72 (s, 3H), 3.22 (m, 1H), 2.91 (m, 2H), 2.60 (s, 3H),2.59 (m, 1H), 2.30 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.40 (m, 4H),1.27 (s, 3H), 1.21 (s, 3H), 1.15 (d, 3H), 1.04 (d, 3H), 0.99 (s, 3H).

Example 7(E)-(7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-8-hydroxy-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione(37)

To a solution of 36 (110 mg, 0.188 mmol) in 5 mL CH₃CN and in a Teflontube is added at rt 1 mL of HF.Pyridine (70/30) and the reaction mixtureis stirred for 2 h at rt. The reaction mixture is washed with a 5%solution of NaHCO₃, extracted 3 times with 10 mL AcOEt and then theorganic layers are dried (MgSO₄). Purification by flash columnchromatography (Hexane/Acetone—90/10 to 50/50) afforded 37 as acolourless oil.

ESI-MS: M(C₂₈H₄₀N₂O₄)=468.6, (M+H)⁺=469.3.

Rf: Hexane/Acetone—30/70:0.35.

¹H NMR (400 MHz, CDCl₃): δ=7.80 (s, 1H), 7.25 (m, 2H), 6.10 (m, 1H),5.60 (m, 1H), 5.50 (m, 1H), 3.80 (m, 1H), 3.80 (s, 3H), 3.30 (m, 1H),2.60 (s, 3H), 2.55 (m, 2H), 2.40 (m, 2H), 2.20 (m, 2H), 1.90 (m, 4H),1.60 (m, 4H), 1.15 (s, 6H), 1.10 (d, 3H), 0.95 (d, 3H).

(7a)—Compound 31

To a solution of CrCl₂ (3.0 g, 24.06 mmol) in 10 mL THF at rt, is addeddropwise over 30 min a mixture of 16 (1.0 g, 3.0 mmol) and CHI_(S) (2.4g, 6.0 mmol) in 60 mL of Dioxane. The reaction mixture is stirred 3 h atit and quenched with 20 mL H₂O, extracted 3 times with 20 mL Et₂O and 3times with 20 mL AcOEt. The combined organic layers are dried (MgSO₄)and concentrated in vacuum. Purification by flash column chromatography(CH₂Cl₂/Acetone—100/0 to 0/100) afforded 31 in a 5/1 ratio.

ESI-MS: M(C₁₉H₂₉N₂OSiI)=456.4, (M+H)⁺=457.0.

Rf: Acetone—100:0.50.

¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.20 (m, 2H), 6.50 (m, 1H),6.00 (dt, 1H), 4.80 (m, 1H), 3.70 (s, 3H), 2.80 (s, 3H), 2.40 (m, 2H),0.95 (s, 9H), 0.05 (s, 3H), −0.18 (s, 3H).

(7b)—Compound 32

To a solution of 31 (1.0 g, 2.191 mmol) in 100 mL of a CH₂Cl₂/MeOH—1/1solution, is added CSA (2.24 g, 9.64 mmol) and the reaction mixture isstirred 2 days at rt. The mixture is quenched with NaHCO₃ (5%) solutionuntil pH-7 and extracted 3 times with 25 mL AcOEt. The combined organiclayers are dried (MgSO₄) and concentrated in vacuum. Purification byflash column chromatography (CH₂Cl₂/MeOH—100/0 to 95/5) afforded 32.Crystallization in CH₂Cl₂/Hexane—1/1 with 3 drops of MeOH afforded 32 ina 15/1 ratio as white crystals.

ESI-MS: M(C₁₃H₁₅N₂OI)=342.2, (M+H)⁺=343.0.

Rf: Hexane/Acetone—50/50:0.25.

¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.20 (m, 2H), 6.50 (m, 1H),6.10 (d, 1H), 4.80 (m, 1H), 3.75 (s, 3H), 2.65 (s, 3H), 2.55 (m, 2H).

(7c)—Compound 33

To a solution of 32 (0.6 g, 1.753 mmol) in 8 mL DMF at 0° C. is addedimidazole (0.36 g, 5.26 mmol) followed by TESCI (0.44 mL, 2.63 mmol).The mixture is stirred 1h30 at 0° C. and then is quenched with H₂O,extracted 3 times with 20 mL Et₂O. The combined organic layers are dried(MgSO₄) and concentrated in vacuum. Purification by flash columnchromatography (Hexane/Acetone—90/10) afforded 33 as colourless oil.

ESI-MS: M(C₁₉H₂₉N₂OSiI)=456.4, (M+H)⁺=457.1.

Rf: Hexane/Acetone—50/50:0.67.

¹H NMR (400 MHz, CDCl₃): δ=7.58 (s, 1H), 7.20 (m, 2H), 6.50 (m, 1H),6.00 (dt, 1H), 4.80 (m, 1H), 3.70 (s, 3H), 2.80 (s, 3H), 2.40 (m, 2H),0.95 (t, 9H), 0.50 (q, 6H).

(7d)—Compound 34

To a 0.5M solution of 9-BBN in 2 mL THF (6.57 mL, 3.286 mmol) is addeddropwise 7 (0.63 g, 1.577 mmol) in 5 mL THF at rt. After 2 h TLCanalysis revealed the complete consumption of the starting olefin. In aseparate flask, containing vinyl iodide (0.6 g, 1.314 mmol) in 5 mL DMFwere added successively, CsCO₃ (0.85 g, 2.63 mmol), AsPh₃ (80 mg, 0.263mmol), Pd(dppf)₂Cl₂ (192 mg, 0.263 mmol) and H₂O (0.71 mL, 39.43 mmol).In first solution is added H₂O (0.24 mL, 13.14 mmol) to quench theexcess 9-BBN and the alkyl borane solution is added rapidly by syringeto the solution containing the vinyl iodide 33. The reaction mixture isstirred at rt for 2 h and quenched with H₂O, extracted 3 times with 20mL CH₂Cl₂. The combined organic layers are dried (MgSO₄) andconcentrated in vacuum. Purification by flash column chromatography(Hexane/Acetone—90/10 to 50/50) afforded 34 as an oil.

ES1-MS: M(C₄₁H₇₂N₂O₅Si₂)=729.2, (M+H)⁺=730.2.

Rf: Hexane/Acetone—70/30:0.27.

¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.20 (m, 2H), 5.40 (m, 2H),4.70 (t, 1H), 3.80 (m, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.15 (m, 1H),2.60 (s, 3H), 2.40 (m, 2H), 2.20 (m, 2H), 1.90 (m, 2H), 1.80 (m, 6H),1.30 (m, 4H), 1.20 (s, 3H), 1.10 (s, 3H), 1.05 (d, 3H), 0.95 (d, 3H),0.93 (s, 9H), 0.85 (t, 9H), 0.50 (q, 6H), 0.05 (s, 6H).

(7e)—Compound 35

To a solution of 34 (0.27 g, 0.37 mmol) in 10 mL i-PrOH/H₂O —4/1 isadded LION (54 mg, 2.22 mmol) and the mixture is heated at 60° C. for 6h. After cooling to rt, the solution is quenched with a saturatedsolution of NH₄Cl, extracted twice with 10 mL CH₂Cl₂ and twice with 10mL AcOEt. The combined organic layers are dried (MgSO₄) and concentratedin vacuum. Purification by flash column chromatography (CH₂Cl₂/MeOH—95/5to 70/30) afforded 35 as a colourless oil.

ESI-MS: M(C₃₄H₅₆N₂O₅Si)=600.9, (M+H)⁺=601.2.

Rf: Hexane/Acetone—30/70:0.27.

¹H NMR (400 MHz, CDCl₃): δ=7.65 (s, 1H), 7.25 (m, 2H), 5.50 (m, 1H),5.30 (m, 1H), 4.80 (t, 1H), 3.80 (m, 1H), 3.70 (s, 3H), 3.20 (m, 1H),2.60 (s, 3H), 2.45 (m, 2H), 2.25 (m, 2H), 1.90 (m, 2H), 1.80 (m, 6H),1.40 (m, 4H), 1.20 (s, 3H), 1.10 (s, 3H), 1.05 (d, 3H), 0.95 (d, 3H),0.94 (s, 9H), 0.05 (s, 6H).

(7f)—Compound 36(E)-(7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-5,5,7,8,9-pentamethyl-oxacyclohexadec-13-ene-2,6-dione

To a solution of 35 (160 mg, 0.266 mmol) in 7 mL THF at 0° C. is addedtriethylamine (0.22 mL, 1.6 mmol) followed by trichlorobenzoylchloride(0.21 mL, 1.33 mmol). After stirring for 20 min at rt, the solution isdiluted with 20 mL dry toluene and the resulting solution is addedslowly in 1 h to a previously prepared solution of DMAP (0.32 mg, 2.66mmol) in 170 mL toluene. The reaction mixture is stirred at rt for 1 hand then concentrated in vacuum. The crude product is purified by flashcolumn chromatography (Hexane/Acetone—90/10 to 50/50) to afford 36 as acolourless oil.

ESI-MS: M(C₃₄H₅₄N₂O₄Si)=582.9, (M+H)⁺=583.2.

Rf: Hexane/Acetone—30/70:0.38.

¹H NMR (400 MHz, CDCl₃): δ=7.65 (s, 1H), 7.20 (2s, 2H), 6.05 (m, 1H),5.60 (m, 1H), 5.50 (m, 1H), 3.80 (m, 1H), 3.70 (s, 3H), 3.20 (m, 1H),2.60 (s, 3H), 2.40 (m, 2H), 2.25 (m, 2H), 2.00 (m, 2H), 1.80 (m, 6H),1.40 (m, 4H), 1.20 (s, 3H), 1.20 (s, 3H), 1.15 (d, 3H), 0.95 (d, 3H),0.94 (s, 9H), 0.10 (s, 3H), 0.05 (s, 3H).

Example 8(1S,3S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione(38)

To a solution of 37 (30 mg, 0.064 mmol) in 1 mL CH₃CN/DMM—1/1 at rt wereadded successively 0.6 mL of a buffer solution (Na₂B₄O₇.10H₂O [0.05M] inNa₂EDTA [4.10⁻⁴M]), Bu₄N(HSO₄) (0.9 mg, 0.0025 mmol) andfructose-derived ketone (13.2 mg, 0.051 mmol). The reaction mixture iscooled to 0° C. and were added separately, in a same time over 1h30,Oxone® (55.1 mg, 0.089 mmol) in 0.8 mL Na₂EDTA and K₂CO₃ (51.3 mg, 0.371mmol) in 0.8 mL H₂O. The solution is stirred at 0° C. for 3 h and thenis quenched with H₂O, extracted 3 times with 10 mL AcOEt. The combinedorganic layers are dried (MgSO₄) and concentrated in vacuum.Purification by flash column chromatography (Hexane/Acetone/MeOH—70/30/0to 45/50/5) afforded 38, 76% conversion.

ESI-MS: M(C₂₈H₄₀N₂O₄)=484.6, (M+H)⁺=485.3.

Rf: Hexane/Acetone—30/70:0.22.

¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.25 (m, 2H), 6.10 (m, 1H),3.80 (m, 1H), 3.75 (s, 3H), 3.25 (m, 1H), 2.90 (m, 2H), 2.60 (s, 3H),2.40 (m, 2H), 2.35 (m, 2H), 2.20 (m, 2H), 1.90 (m, 6H), 1.60 (m, 4H),1.15 (s, 6H), 1.20 (d, 3H), 1.00 (d, 3H).

Example 916-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-4,8-dihydroxy-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione(Compound 43)

To a 50 ml plastic tube, equipped with a magnetic stir bar, aresuccessively added 42 (170 mg) and 10 ml of acetonitrile. To thissolution is rapidly added HF-Pyridine complex (2 ml). The reaction ismonitored by TLC (CH₂Cl₂/MeOH:95/5) and the mixture is stirred at roomtemperature for 20 h. The reaction mixture is then carefully added dropwise to an Erlenmeyer containing CH₂Cl₂ (30 ml) and (30 ml) andsaturated aqueous sodium bicarbonate. The pH of the aqueous phase isadjusted to 9 by addition of pure sodium bicarbonate. The two layers arethen separated by decantation and the aqueous phase is exctracted threetimes with CH₂Cl₂ (30 ml). After drying with magnesium sulfate, thesolvents are removed under vacuo and the crude mixture is purified byflash chromatography (CH₂Cl₂/methanol:95/5 to 90/10) to finally give 43as a white solid.

ESI-MS: 485.3 (M+H)⁺.

Rf=0.24 (CH₂Cl₂/MeOH:95/5).

¹H-NMR (400 MHz, CD₃OD/ppm): 7.62 (s, 1H), 7.37 (AB, 10 Hz, 2H), 5.88(m, 1H), 5.50 (m, 2H), 4.27 (m, 1H), 3.77 (s, 3H), 3.68 (m, 1H), 3.27(q, 8 Hz, 1H), 2.95 (m, 1H), 2.59 (s, 3H), 2.50-2.28 (m, 4H), 2.01 (m,1H), 1.69 (m, 1H), 1.60-1.43 (m, 2H), 1.37-1.10 (m, 2H), 1.30 (s, 3H),1.21 (d, 8 Hz, 3H), 1.05 (d, 7 Hz, 3H), 1.02 (s, 3H), 0.9 (m, 1H).

(9a)—Compound 40

Flask A: To a solution of 39 (265 mg) in 3.5 ml THF is added 9-BBN (2 mlof a 0.5M solution in THF) drop wise at 0° C. After the end of theaddition, the ice bath is removed and the reaction mixture is allowed towarm up to room temperature. The reaction is monitored by TLC and iscomplete after 100 minutes. The excess of 9-BBN is quenched by additionof 50 μl of distilled water.

Flask B: In a 25 ml three-necked round bottomed flask, are successivelyadded the vinyl iodide 18 (142 mg) and 5 ml of DMF. The solution iscooled down to 0° C. and Cesium carbonate (234 mg), triphenylarsine (25mg), the Palladium catalyst (68 mg) and distilled water (200 μl) aresuccessively added. The content of Flask A is then rapidly added (30sec) under vigorous stirring. After 10 minutes at 0° C., the ice bath isremoved and the reaction mixture is allowed to warm up to roomtemperature. The reaction is monitored by MS and is complete after 1h15.The mixture is then poured in a 100 ml Erlenmeyer containing 50 ml ofdiethyl ether and 50 ml of a saturated aqueous ammonium chloride. Thetwo layers are separated by decantation and the aqueous phase isextracted twice with 50 ml of diethyl ether. The organic phases arejoined and dried with magnesium sulfate. Evaporation of the solventsunder vacuo yielded a brown oil which is purified by flashchromatography (Hexanes/Acetone:80/20 to 60/40) to finally yield 40 as athick yellow oil.

ESI-MS: 745.2 (M+H)⁺.

Rf=0.15 (Hex/Acetone:70/30).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.69 (s, 1H), 7.38 (AB, 2H), 5.53 (m, 1H),5.37 (m, 1H), 4.81 (dd, 1H), 4.39 (dd, 1H), 3.81 (s, 3H), 3.77 (dd, 1H),3.70 (s, 3H), 3.13 (m, 1H), 2.79 (s, 3H), 2.69-2.46 (m, 2H), 2.42 (A ofABX, 1H), 2.27 (B of ABX, 1H), 2.02 (m, 2H), 1.43-1.0 (m, 6H), 1.24 (s,3H), 1.07 (s, 3H), 1.04 (d, 7 Hz, 3H), 0.91 (s, 9H), 0.89 (d, 7 Hz, 3H),0.88 (s, 9H), 0.10 (s, 3H), 0.06 (s, 6H), 0.03 (s, 3H).

(9b)—Compound 41

Lithium hydroxide (39 mg) is added to a solution of 40 (200 mg) in amixture of isopropanol (4.8 ml) and water (1.2 ml). The reaction mixtureis then warmed up to 60° C. and stirred for 2 h30. The mixture is thenpoured into an Erlenmeyer containing 40 ml of CH₂Cl₂ and 30 ml of water.The mixture is then acidified to pH 5 by a slow addition of Hydrochloricacid 0.1 N under vigorous stirring (approx 16 ml). The two layers areseparated by decantation and the aqueous phase is extracted three timeswith 20 ml of CH₂Cl₂. The organic phases are joined and after dryingwith magnesium sulfate, removing of the solvents under vacuo, the crudeis purified by flash chromatography (Hexanes/acetone:50/50 to 0/100) toyield 41, as a white foam.

ESI-MS: 731.3 (M+H)⁺.

Rf=0.12 (CH₂Cl₂/MeOH:95/5).

¹H-NMR (400 MHz, CD₃OD/ppm): 7.53 (s, 1H), 7.34 (AB, 2H), 5.39 (m, 2H),4.72 (t, 1H), 4.33 (dd, 1H), 3.77 (s, 3H), 3.74 (dd, 1H), 3.21 (m, 1H),2.60 (s, 3H), 2.54 (m, 2H), 2.43 (A of ABX, 1H), 2.18 (B of ABX, 1H),1.93 (m, 2H), 1.44-0.97 (m, 6H), 1.22 (s, 3H), 1.06 (s, 3H), 1.05 (d,3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.87 (d, 3H), 0.10 (s, 3H), 0.07 (s,3H), 0.06 (s, 3H), 0.05 (s, 3H).

(9c)—Compound 42

Flask A: To a solution of 41 (300 mg) and Triethylamine (345 μl) intetrahydrofuran (10 ml) at 0° C., is rapidly added2,4,6-trichlorobenzoyl chloride (320 μl). After stirring at 0° C. for 15min, the mixture is allowed to warm up to room temperature and stirredfor another 15 minutes.

Flask B: The content of Flask A is slowly added (1h30) to a solution ofDMAP (600 mg) in 300 ml of toluene, under vigorous stirring. After theend of the addition, the mixture is stirred for an additional 30minutes. The solvents are then removed under vacuo and the residue ispurified by flash chromatography (Hexanes/acetone 60/40 to 40/60) toyield the desired product 42, as a white foam.

ESI-MS: 713.1 (M+H)⁺.

Rf=0.37 (CH₂Cl₂/MeOH:95/5).

¹H-NMR (400 MHz, CD₃OD/ppm): 7.56 (s, 1H), 7.31 (AB, 2H), 5.62 (bd, 10Hz, 1H), 5.60-5.40 (m, 2H), 3.99 (d, 9 Hz, 1H), 3.92 (d, 8 Hz, 1H),3.20-2.67 (m, 4H), 2.60 (5, 3H), 2.16 (m, 1H), 1.93 (m, 1H), 1.66 (m,2H), 1.3-0.8 (m, 5H), 1.19 (s, 3H), 1.13 (s, 3H), 1.12 (d, 3H), 1.01 (d,7 Hz, 3H), 0.98 (s, 9H), 0.88 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H), 0.12(s, 3H), −0.04 (s, 3H).

Example 103-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione(Compound 44)

In a 10 ml round bottomed flask are successively introduced distilledwater (7 ml), Pyridine (50 μl) and hydrogen peroxide 30% (700 μl). Apart of this solution (500 μl) is rapidly added in a solution of 43 (57mg) in 2 ml of CH₂Cl₂ and under vigorous stirring, MTO (2 mg) is addedin one portion. After 5 h of stirring, the reaction mixture is addeddropwise to an Erlenmeyer containing methylene chloride (20 ml),distilled water (20 ml) and sodium bicarbonate (1 g) The two layers areseparated by decantation and the aqueous phase is extracted twice withCH₂Cl₂ (20 ml). After drying with magnesium sulfate and removal of thesolvent in vacuo, the crude mixture (a 2:1 diastereomeric mixture) ispurified by preparative HPLC, to finally yield the pure diastereomer 44,as a white powder.

ESI-MS: 501.0 (M+H)⁺.

Rf=0.40 (CH₂Cl₂/MeOH:90/10).

¹H-NMR (400 MHz, DMSO-d6/ppm): 7.57 (s, 1H), 7.40 (A of AB, 8 Hz, 1H)7.26 (B of AB, 8 Hz, 1H), 5.92 (bd, 9 Hz, 1H), 5.10 (bd, 6 Hz, 1H), 4.47(bd, 6 Hz, 1H), 3.94 (m, 1H), 3.72 (s, 3H), 3.51 (m, 1H), 3.13 (m, 2H),2.88 (m, 1H), 2.58-2.34 (m, 2H), 2.52 (s, 3H), 2.16 (m, 1H), 1.98 (m,1H), 1.77-1.10 (m, 5H) 1.15 (s, 3H), 1.05 (d, 6 Hz, 3H), 0.93 (s, 3H),0.92 (d, 3H).

Example 11(E)-(4S,7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-4,8-dihydroxy-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione(48)

To a solution of 47 (80 mg, 0.112 mmol) in 5 mL CH₃CN and in a Teflontube is added at rt 1 mL of HF.Pyridine (70/30) and the reaction mixtureis stirred 6 h at rt. The reaction mixture is washed with a 5% solutionof NaHCO₃ (pH-5), extracted 3 times with 10 mL AcOEt and then theorganic layers are dried (MgSO₄). Purification by flash columnchromatography (Hexane/Acetone—50/50 to 0/100) afforded 48 as whitecrystals.

ESI-MS: M(C₂₈H₄₀N₂O₅)=484.6, (M+H)⁺=485.2.

Rf: Hexane/Acetone—30/70:0.18.

¹H NMR (400 MHz, CD₃OD): δ=7.62 (s, 1H), 7.51 (d, 1H), 7.38 (d, 1H),6.01 (dd, 1H), 5.57 (m, 1H), 5.33 (m, 1H), 4.60 (dd, 1H), 3.90 (s, 3H),3.66 (dd, 1H), 3.42 (m, 1H), 2.68 (m, 2H), 2.65 (s, 3H), 2.50 (m, 2H),2.24 (m, 1H), 1.90 (m, 1H), 1.69 (m, 2H), 1.33 (m, 2H), 1.30 (d, 3H),1.17 (s, 3H), 1.02 (s, 3H), 1.00 (d, 3H).

(11a)—Compound 45

To a 0.5M solution of 9-BBN in 10 mL THF (6.3 mL, 3.149 mmol) is addeddropwise 39 (0.8 g, 1.512 mmol) in 5 mL THF at rt. After 2 h TLCanalysis revealed the complete consumption of the starting olefin. In aseparate flask, containing 33 (0.575 g, 1.260 mmol) in 10 mL DMF wereadded successively, Cs₂CO₃ (0.82 g, 2.519 mmol), AsPh₃ (77 mg, 0.251mmol), Pd(dppf)₂Cl₂ (184 mg, 0.251 mmol) and H₂O (0.68 mL, 37.6 mmol).In first solution is added H₂O (226 μL, 12.6 mmol) to quench the excess9-BBN and the alkyl borane solution is added rapidly by syringe to thesolution containing 39. The reaction mixture is stirred at rt overnightand quenched with H₂O, extracted 3 times with 30 mL Et₂O. The combinedorganic layers are dried (MgSO₄) and concentrated in vacuum.Purification by flash column chromatography (Hexane/Acetone—90/10 to70/30) afforded 45 as colourless oil.

ESI-MS: M(C₄₇H₈₆N₂O₆Si₃)=859.5, (M)⁺=859.3.

Rf: Hexane/Acetone—50/50:0.73.

¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.20 (m, 2H), 5.40 (m, 2H),4.71 (m, 1H), 4.20 (m, 1H), 3.80 (m, 1H), 3.70 (s, 3H), 3.67 (s, 3H),3.17 (m, 1H), 2.60 (s, 3H), 2.40 (m, 2H), 2.35 (m, 2H), 1.95 (m, 2H),1.30 (m, 4H), 1.20 (s, 3H), 1.05 (s, 3H), 1.03 (d, 3H), 0.91 (d, 3H),0.90 (s, 18H), 0.90 (t, 9H), 0.50 (q, 6H), 0.10 (s, 3H), 0.05 (s, 6H),0.03 (s, 3H).

(11b)—Compound 46

To a solution of 45 (50 mg, 0.067 mmol) in 2 mL i-PrOH/H₂O —4/1 is addedLiOH (5 mg, 0.201 mmol) and the mixture is heated 6 h at 50° C. (in).After cooling to rt, the solution is quenched with a saturated solutionof NH₄Cl, extracted twice with 10 mL CH₂Cl₂ and twice with 10 mL Et₂O.The combined organic layers are dried (MgSO₄) and concentrated invacuum. Purification by flash column chromatography(Hexane/Acetone—50/50 to 0/100) afforded 46 as an colourless oil.

ESI-MS: M(C₄₀H₇₀N₂O₆Si₂)=731.2, (M+H)⁺=731.4.

Rf: Hexane/Acetone—50/50:0.46.

¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.30 (m, 2H), 5.45 (m, 1H),5.35 (m, 1H), 4.80 (m, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.74 (s, 3H),3.20 (m, 1H), 2.65 (s, 3H), 2.45 (m, 2H), 2.35 (m, 2H), 1.98 (m, 2H),1.40 (m, 4H), 1.20 (s, 3H), 1.10 (s, 3H), 1.05 (d, 3H), 0.95 (d, 3H),0.94 (s, 18H), 0.09 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H).

(11c) Compound 47(E)-(4S,7R,8S,9S,16S)-4,8-Bis-(tert-butyl-dimethyl-silanyloxy)-16-(1,2-dimethyl-1H-benzoimidazol-5-yl)-5,5,7,9-tetramethyl-oxacyclohexadec-13-ene-2,6-dione

To a solution of 46 (345 mg, 0.471 mmol) in 12 mL THF at 0° C. is addedtriethylamine (0.395 mL, 2.831 mmol) followed bytrichlorobenzoylchloride (0.37 mL, 2.359 mmol). After stirring for 20min at rt, the solution is diluted with 20 mL dry toluene and theresulting solution is added slowly in 2 h to a previously preparedsolution of DMAP (0.575 g, 4.718 mmol) in 300 mL toluene. The reactionmixture is stirred at rt for 30 min and then concentrated in vacuum. Thecrude product is purified by flash column chromatography(Hexane/Acetone—90/10 to 70/30) to afford 47 as colourless oil.

ESI-MS: M(C₄₀H₆₈N₂O₅Si₂)=713.2, (M)⁺=713.4.

Rf: Hexane/Acetone—30/70:0.56.

¹H NMR (400 MHz, CDCl₃): δ=7.62 (s, 1H), 7.26 (m, 2H), 5.87 (m, 1H),5.52 (m, 1H), 5.37 (m, 1H), 4.40 (m, 1H), 3.97 (m, 1H), 3.70 (s, 3H),3.17 (m, 1H), 2.60 (s, 3H), 2.60 (m, 2H), 2.55 (m, 2H), 1.92 (m, 2H),1.45 (m, 4H), 1.20 (s, 3H), 1.10 (s, 3H), 1.05 (d, 3H), 0.95 (d, 3H),0.94 (s, 9H), 0.84 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.04 (s, 3H),0.01 (s, 3H).

Example 12(1S,3S,7S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione(49)

To a solution of 48 (24 mg, 0.0495 mmol) in 0.75 mL CH₃CN/DMM—1/1 at rtwere added successively 0.46 mL of a buffer solution (Na₂B₄O₇.10H₂O[0.05M] in Na₂EDTA [4.10⁻⁴M]), Bu₄N(HSO₄) (0.67 mg, 0.0019 mmol) andfructose-derived ketone (10.2 mg, 0.0396 mmol). The reaction mixture iscooled to 0° C. and were added separately, in a same time over 1 h30,Oxone® (42.6 mg, 0.089 mmol) in 0.6 mL Na₂EDTA and K₂CO₃ (39.7 mg, 0.287mmol) in 0.6 mL H₂O. The solution is stirred 1h30 at 0° C. and then isquenched with H₂O, extracted 3 times with 10 mL AcOEt. The combinedorganic layers are dried (MgSO₄) and concentrated in vacuum.Purification by flash column chromatography(Hexane/Acetone/MeOH—50/45/5) afforded 49 in a 8/1 ratio as whitecrystals.

ESI-MS: M(C₂₈H₄₀N₂O₆)=500.6, (M+H)⁺=501.2.

Rf: Hexane/Acetone—30/70:0.17.

¹H NMR (400 MHz, CD₃OD): δ=7.62 (s, 1H), 7.41 (d, 1H), 7.35 (d, 1H),6.05 (dd, 1H), 4.23 (dd, 1H), 3.88 (s, 3H), 3.72 (dd, 1H), 3.45 (m, 1H),2.68 (m, 2H), 2.60 (s, 3H), 2.49 (m, 21-1), 2.20 (m, 1H), 2.00 (m, 1H),1.90 (m, 2H), 1.40 (m, 2H), 1.30 (s, 3H), 1.20 (d, 3H), 1.02 (s, 3H),1.00 (d, 3H).

Example 13(3E,13E)-(7R,8S,9S,16S)-16-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-8-hydroxy-5,5,7,9-tetramethyl-oxacyclohexadeca-3,13-diene-2,6-dione(55)

To a solution of 54 (12 mg, 0.0206 mmol) in 1 mL CH₃CN and in a Teflontube is added at it 0.2 mL of HF.Pyridine (70/30) and the reactionmixture is stirred 6 h at rt. The reaction mixture is washed with a 5%solution of NaHCO₃, extracted 3 times with 10 mL AcOEt and then theorganic layers are dried (MgSO₄). Purification by flash columnchromatography (CH₂Cl₂/MeOH —98/2) afforded 55 as white crystals.

ESI-MS: M(C₂₈H₃₈N₂O₄)=466.6, (M+H)⁺=467.1.

Rf: Hexane/Acetone—50/50:0.18.

¹H NMR (400 MHz, CDCl₃): δ=7.71 (s, 1H), 7.20 (s, 2H), 6.91 (d, 1H),6.15 (m, 1H), 6.01 (d, 1H), 5.45 (m, 2H), 3.70 (s, 3H), 3.60 (m, 1H),3.18 (m, 1H), 2.60 (s, 3H), 2.17 (m, 2H), 1.97 (m, 2H), 1.60 (m, 2H),1.40 (m, 2H), 1.34 (s, 3H), 1.18 (s, 3H), 1.15 (d, 3H), 0.95 (d, 3H).

(13a)—Compound 50

To a 0.5M solution of 9-BBN in 3 mL THF (2.2 mL, 1.095 mmol) is addeddropwise 39 (0.28 g, 0.526 mmol) in 2 mL THF at rt. After 2 h TLCanalysis revealed the complete consumption of the starting olefin. In aseparate flask, containing 31 (0.2 g, 0.438 mmol) in 3 mL DMF were addedsuccessively, Cs₂CO₃ (0.28 g, 0.876 mmol), AsPh₃ (27 mg, 0.087 mmol),Pd(dppf)₂Cl₂ (64 mg, 0.087 mmol) and H₂O (0.24 mL, 13.143 mmol). Infirst solution is added H₂O (80 pt, 4.381 mmol) to quench the excess9-BBN and the alkyl borane solution is added rapidly by syringe to thesolution containing 31. The reaction mixture is stirred overnight at itand quenched with H₂O, extracted 3 times with 25 mL Et₂O. The combinedorganic layers are dried (MgSO₄) and concentrated in vacuum.Purification by flash column chromatography (CH₂Cl₂—100 thenHexane/Acetone—70/30) afforded 50.

ESI-MS: M(C₄₇H₈₆N₂O₆Si₃)=859.4, (M⁺)⁺=899.1.

Rf: Hexane/Acetone—50/50:0.70.

¹H NMR (400 MHz, CDCl₃): δ=7.63 (s, 1H), 7.28 (m, 2H), 5.40 (m, 2H),4.75 (m, 1H), 4.40 (m, 1H), 3.80 (s, 3H), 3.79 (m, 1H), 3.62 (s, 3H),3.17 (m, 1H), 2.70 (s, 3H), 2.40 (m, 2H), 2.35 (m, 2H), 1.95 (m, 2H),1.80 (m, 2H), 1.50 (m, 2H), 1.20 (s, 3H), 1.10 (s, 3H), 1.07 (d, 3H),0.91 (s, 9H), 0.90 (d, 3H), 0.88 (s, 18H), 0.10 (s, 3H), 0.05 (s, 6H),0.03 (s, 6H), −0.18 (s, 3H).

(13b)—Compound 51

To a solution of 50 (250 mg, 0.291 mmol) in 6 mL THF under argon isadded a 1M solution of TBAF (0.87 mL, 0.873 mmol) and the reactionmixture is stirred 8 h at rt. The solution is washed with a 5% solutionof NaHCO₃ and extracted 3 times with 25 mL Et₂O. The combined organiclayers are dried (MgSO₄) and concentrated in vacuum. Purification byflash column chromatography (Hexane/Acetone—90/10 to 50/50) afforded 51as a colourless oil.

ESI-MS: M(C₄₁H₇₀N₂O₅Si₂)=727.2, (M+H)⁺=729.3.

Rf: Hexane/Acetone—50/50:0.46.

¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.21 (m, 2H), 7.06 (d, 1H),5.90 (d, 1H), 5.40 (m, 2H), 4.72 (m, 1H), 3.80 (m, 1H), 3.76 (s, 3H),3.73 (s, 3H), 3.05 (m, 1H), 2.60 (s, 3H), 2.40 (m, 2H), 1.92 (m, 2H),1.30 (m, 2H), 1.29 (s, 3H), 1.28 (s, 3H), 1.05 (d, 3H), 0.89 (s, 9H),0.88 (d, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 6H), 0.02 (s, 6H),−0.18 (s, 3H).

(13c)—Compound 52

To a solution of 51 (50 mg, 0.0687 mmol) in 2 mL THF/H₂O—7/1 is addedLiOH (10 mg, 0.412 mmol) and the mixture is stirred 25 h at rt. Thesolution is quenched with a 2% solution of KHSO₄ (until pH-5) extracted3 times with 10 mL AcOEt. The combined organic layers are dried (MgSO₄)and concentrated in vacuum. Purification by flash column chromatography(Hexane/Acetone—90/10 to 50/50) afforded 52 as colourless oil.

ESI-MS: M(C₄₀H₆₈N₂O₅Si₂)=713.1, (M+H)⁺=713.3.

Rf: Hexane/Acetone—50/50:0.37.

¹H NMR (400 MHz, CD₃OD): δ=7.58 (s, 1H), 7.52 (d, 1H), 7.38 (d, 1H),7.04 (d, 1H), 5.90 (d, 1H), 5.40 (m, 2H), 4.82 (m, 1H), 3.81 (s, 3H),3.80 (m, 1H), 3.05 (m, 1H), 2.63 (s, 3H), 2.40 (m, 2H), 1.92 (m, 2H),1.30 (m, 2H), 1.29 (s, 3H), 1.25 (s, 3H), 1.05 (d, 3H), 0.89 (s, 9H),0.88 (d, 3H), 0.88 (s, 9H), 0.05 (s, 6H), 0.04 (s, 3H), −0.16 (s, 3H).

(13d)—Compound 53

To a solution of 52 (30 mg, 0.042 mmol) in 2 mL THF under argon is addeda 1M solution of TBAF (0.25 mL, 0.252 mmol) and the reaction mixture isstirred 24 h at rt. The solution is washed with a 5% solution of NaHCO₃and extracted 3 times with 25 mL AcOEt. The combined organic layers aredried (MgSO₄) and concentrated in vacuum. Purification by flash columnchromatography (CH₂Cl₂/MeOH—95/5) afforded 53, as an oil.

ESI-MS: M(C₃₄H₅₄N₂O₅Si)=598.9, (M+H)⁺=599.2.

Rf: CH₂Cl₂/MeOH—90/10:0.29.

¹H NMR (400 MHz, CD₃OD): δ=7.58 (s, 1H), 7.41 (d, 1H), 7.28 (d, 1H),6.95 (d, 1H), 5.91 (d, 1H), 5.40 (m, 2H), 4.75 (m, 1H), 3.80 (s, 3H),3.80 (m, 1H), 3.15 (m, 1H), 2.60 (s, 3H), 2.45 (m, 2H), 1.92 (m, 2H),1.40 (m, 2H), 1.27 (s, 3H), 1.24 (s, 3H), 1.03 (d, 3H), 0.89 (s, 9H),0.85 (d, 3H), 0.05 (s, 6H).

(13e)—Compound 54(3E,13E)-(7R,8S,9S,16S)-8-(tert-Butyl-dimethyl-silanyloxy)-16-(1,2-dimethyl-1H-benzoimidazol-5-yl)-5,5,7,9-tetramethyl-oxacyclohexadeca-3,13-diene-2,6-dione

To a solution of 53 (20 mg, 0.033 mmol) in 2 mL THF at 0° C. is addedtriethylamine (28 μL, 0.20 mmol) followed by trichlorobenzoylchloride(26 μL, 0.167 mmol). After stirring for 20 min at rt, the solution isdiluted with 5 mL dry toluene and the resulting solution is added slowlyin 1 h to a previously prepared solution of DMAP (41 mg, 0.334 mmol) in20 mL toluene. The reaction mixture is stirred at rt for 30 min and thenconcentrated in vacuum. The crude product is purified by flash columnchromatography (CH₂Cl₂/MeOH —98/2) to afford 54 as white crystals.

ESI-MS: M(C₃₄H₅₂N₂O₄Si)=580.9, (M+H)⁺=581.2.

Rf: Hexane/Acetone—50/50:0.37.

¹H NMR (400 MHz, CDCl₃): δ=7.71 (s, 1H), 7.25 (s, 2H), 6.88 (d, 1H),6.20 (m, 1H), 6.05 (d, 1H), 5.50 (m, 2H), 3.70 (s, 3H), 3.70 (m, 1H),3.08 (m, 1H), 2.60 (s, 3H), 2.18 (m, 2H), 1.98 (m, 2H), 1.60 (m, 2H),1.40 (m, 2H), 1.29 (s, 3H), 1.20 (s, 3H), 1.10 (d, 3H), 0.95 (d, 3H),0.84 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 14(E)-(1S,3S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-1′-hydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadec-6-ene-5,9-dione(56)

To a solution of 55 (40 mg, 0.0857 mmol) in 1.3 mL CH₃CN/DMM —1/1 at rtwere added successively 0.8 mL of a buffer solution (Na₂B₄O₇.10H₂O[0.05M] in Na₂EDTA [4.10⁻⁴M]), Bu₄N(HSO₄) (1.2 mg, 0.003 mmol) andfructose-derived ketone (17.7 mg, 0.0685 mmol). The reaction mixture iscooled to 0° C. and were added separately, in a same time over 1h30,Oxone® (73.8 mg, 0.120 mmol) in 1 mL Na₂EDTA and K₂CO₃ (68.7 mg, 0.497mmol) in 1 mL H₂O. The solution is stirred 3 h at 0° C. and then isquenched with H₂O, extracted 3 times with 10 mL AcOEt. The combinedorganic layers are dried (MgSO₄) and concentrated in vacuum.Purification of crude product by prep-HPLC afforded 56, 50% conversionin a 8/1 ratio.

ESI-MS: M(C₂₈H₃₈N₂O₅)=482.6, (M+H)⁺=483.2.

Rf: Hexane/Acetone—30/70:0.23.

¹H NMR (400 MHz, CDCl₃): δ=7.72 (s, 1H), 7.27 (s, 2H), 6.91 (d, 1H),6.37 (d, 1H), 6.05 (d, 1H), 3.80 (m, 1H), 3.77 (s, 3H), 3.19 (m, 1H),2.90 (m, 2H), 2.61 (s, 3H), 2.58 (m, 2H), 1.97 (m, 4H), 1.60 (m, 2H),1.40 (m, 2H), 1.43 (s, 3H), 1.20 (s, 3H), 1.18 (d, 3H), 1.01 (d, 3H).

Example 153-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4-oxa-bicyclo[14.1.0]heptadecane-5,9-dione(compound 64)

To a 50 ml plastic tube, equipped with a magnetic stir bar, aresuccessively added 63 (60 mg), 5 ml of acetonitrile. To this solution israpidly added HF-Pyridine complex (1 ml). The reaction is monitored byTLC (CH₂Cl₂/MeOH: 95/5) and the mixture is stirred at room temperaturefor 5 h. The reaction mixture is then carefully added dropwise to anErlenmeyer containing methylene chloride (30 ml), distilled water (30ml) and sodium bicarbonate (5 g).

The two layers are separated by decantation and the aqueous phase isextracted three times with methylene chloride (20 ml). After drying withmagnesium sulfate, the solvents are removed under vacuo and the crudemixture is purified by flash chromatography (CH₂Cl₂/MeOH:95/5) followedby preparative HPLC to finally give the pure diastereoisomer 64, as awhite powder.

ESI-MS: 499.1 (M+H)⁺.

HPLC: Rf=7.02 min (method 1).

Rf=0.25 (CH₂Cl₂/MeOH:95/5)

¹H-NMR (400 MHz, DMSO-d6/ppm): 7.50 (s, 1H), 7.37 (d, 8 Hz, 1H), 7.29(d, 8 Hz, 1H), 5.75 (dd, 3.9 Hz, 1H), 5.08 (d, 6 Hz, 1H), 4.42 (d, 6 Hz,1H), 3.95 (m, 1H), 3.69 (s, 3H), 3.53 (m, 1H), 3.12 (m, 1H), 2.55-2.30(m, 2H), 2.50 (s, 3H), 2.03 (A of ABX, 1H), 1.75 (B of ABX, 1H),1.52-1.13 (m, 7H), 1.21 (s, 3H), 1.05 (d, 6 Hz, 3H), 0.95 (s, 3H), 0.93(d, 3H), 0.90 (m, 1H), 0.70 (m, 1H), 0.57 (m, 1H), −0.32 (m, 1H).

(15a)—Compound 58

Sodium bis(trimethylsilyl)-amide (3.6 ml of a 1M THF solution) is slowlyadded at room temperature to a suspension of the finely crushediodomethyl-triphenylphosphonium iodide salt (2.0 g) in 10 ml THF. Thesolution becomes quickly orange. After the end of the addition (−10min), the mixture is cooled down to −78° C. and the aldehyde 57 (1.0 g)in of THF (5 ml) is added dropwise. After 60 min stirring at −78° C.,the reaction is quenched by the addition of a saturated solution ofAmmonium chloride (20 ml) under vigorous stirring. The mixture is thenallowed to warm up to room temperature and CH₂Cl₂ is added (50 ml). Thetwo layers are separated by decantation and the aqueous phase isextracted twice with CH₂Cl₂ (20 ml). After drying of the joined organicphases with magnesium sulfate and evaporation of the solvents undervacuo, the residue is taken in hexane (20 ml) in order to precipitatethe triphenylphosphine oxide. The precipitate is filtered off and washedwith hexane (2 ml) and the filtrate is kept at 4° C. overnight tocomplete the precipitation of the triphenylphosphine oxide. The solventis removed under vacuo and the crude is purified by Flash chromatography(EtOAc) to yield 58 as a clear oil.

ESI-MS: 456.9 (M+H)⁺.

Rf=0.54 (CH₂Cl₂/MeOH:90/10).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.75 (s, 1H), 7.23 (m, 2H), 6.22 (m, 2H),4.91 (m, 1H), 3.74 (s, 3H), 2.67-2.49 (m, 2H), 2.63 (s, 3H), 0.90 (s,9H), 0.05 (s, 3H) −0.10 (s, 3H).

(15b)—Compound 59

Camphorsulfonic acid (1.87 g) is added carefully (˜10 installments) in asolution of 58 (914 mg) in CH₂Cl₂ (50 ml) and methanol (50 ml) at 0° C.The mixture is then allowed to warm up to room temperature and isstirred for 17 h. The mixture is then carefully poured in an Erlenmeyercontaining distilled water (150 ml) and sodium bicarbonate (1.34 g)under vigorous stirring. The layers are separated and the aqueous phaseis extracted three times with CH₂Cl₂ (50 ml). The organic phases arejoined, dried over sodium sulfate and the solvents are removed undervacuo. The crude is purified by flash chromatography (CH₂Cl₂/MeOH:95/5)in order to give 59, a white solid.

ESI-MS: 343.0 (M+H)⁺.

Rf=0.35 (CH₂Cl₂/MeOH:90/10).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.66 (s, 1H), 7.29 (m, 2H), 6.29 (m, 2H),4.97 (m, 1H), 3.75 (s, 3H), 2.78-2.62 (m, 2H), 2.62 (s, 3H).

(15c)—Compound 60

Flask A: To a solution of 39 (1.16 g) in 20 ml THF is added 9-BBN (8.8ml of a 0.5M solution in THF) drop wise at 0° C. After the end of theaddition, the ice bath is removed and the reaction mixture is allowed towarm up to room temperature. The reaction is monitored by TLC and iscomplete after 120 minutes. The excess of 9-BBN is quenched by additionof 200 μl of distilled water.

Flask B: In a 100 ml three-necked round bottomed flask, are successivelyadded the vinyl iodide 59 (600 mg) and 20 ml of DMF. The solution iscooled down to 0° C. and Cesium carbonate (1.19 g), triphenylarsine (107mg), the Palladium catalyst (297 mg) and distilled water (880 μl) aresuccessively added. The content of Flask A is then rapidly added (30sec) under vigorous stirring. After 10 minutes at 0° C., the ice bath isremoved and the reaction mixture is allowed to warm up to roomtemperature. The reaction is monitored by MS and is complete after. Themixture is then poured in an Erlenmeyer containing 300 ml of diethylether and 300 ml of a saturated aqueous ammonium chloride. The twolayers are separated by decantation and the aqueous phase is extractedtwice with 200 ml of diethyl ether. The organic phases are joined anddried with magnesium sulfate. Evaporation of the solvents under vacuoyielded a brown oil which is purified by flash chromatography(Hexanes/Acetone:80/20 to 60/40) to finally yield 60 as a thick yellowoil.

ESI-MS: 745.2 (M+H)⁺.

Rf=0.45 (CH₂Cl₂/MeOH:90/10).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.64 (s, 1H), 7.26 (m, 2H), 5.53 (m, 1H),5.40 (m, 1H), 4.83 (m, 1H), 4.40 (dd, 1H), 3.77 (dd, 1H), 3.73 (s, 3H),3.68 (s, 3H), 3.14 (m, 1H), 2.71-2.48 (m, 2H), 2.63 (s, 3H), 2.45 (A ofABX, 1H), 2.29 (B of ABX, 1H), 2.05 (m, 2H), 1.46-1.0 (m, 5H), 1.25 (s,3H), 1.08 (s, 3H), 1.05 (d, 7 Hz, 3H), 0.92 (s, 9H), 0.89 (d, 3H), 0.88(s, 9H), 0.10 (s, 3H), 0.06 (s, 6H), 0.02 (s, 3H).

(15d)—Compound 61

To a solution of Et₂Zn (3 ml of a 1.0M solution in hexane) in CH₂Cl₂ (6ml), is slowly added (15 min), at −10° C., a solution of TFA (228 μl) inCH₂Cl₂ (3 ml). The reaction mixture is stirred for another 15 minutesand a solution of diiodomethane (240 μl) in CH₂Cl₂ (3 ml) is added.After stirring for 30 minutes, 60 (250 mg) in CH₂Cl₂ (3 ml) is addeddrop wise and the mixture is stirred at −10° C. for another 30 minutes.The reaction is then quenched by addition of a aqueous saturatedammonium chloride solution (15 ml). The two layers are separated bydecantation and the aqueous phase is extracted three times with CH₂Cl₂.The organic phases are joined, dried over MgSO₄ and the solvents areevaporated. The crude is then purified by flash chromatography(CH₂Cl₂/MeOH:95/5) to give 61, as a white foam.

ESI-MS: 759.3 (M+H)⁺.

Rf=0.45 (CH₂Cl₂/MeOH:90/10).

¹H-NMR (400 MHz, C₆D₆/ppm): 8.04 (s, 1H), 7.43 (d, 5 Hz, 1H), 6.91 (d, 5Hz, 1H), 4.89 (m, 1H), 4.63 (dd, 1H), 3.98 (dd, 1H), 3.33 (s, 3H), 3.19(m, 1H), 2.62 (s, 3H), 2.58 (A of ABX, 1H), 2.31 (B of ABX, 1H),2.10-2.0 (m, 1H), 2.05 (s, 3H), 1.78 (m, 1H), 1.62-1.0 (m, 9H), 1.14 (d,7 Hz, 3H), 1.12 (s, 3H), 1.11 (s, 3H), 1.04 (s, 9H), 1.02 (d, 3H), 0.96(s, 9H), 0.81 (m, 1H), 0.62 (m, 2H), 0.17 (s, 3H), 0.15 (s, 3H), 0.14(s, 3H), 0.12 (s, 3H), −0.15 (m, 1H).

(15e)—Compound 62

Lithium hydroxide (77 mg) is added to a solution of 61 (400 mg) in amixture of isopropanol (12 ml) and water (3 ml). The reaction mixture isthen warmed up to 60° C. and stirred for 2 h. The mixture is then pouredinto an Erlenmeyer containing 30 ml of CH₂Cl₂ and 30 ml of water. Themixture is then acidified to pH 5 by a slow addition of Hydrochloricacid 1M under vigorous stirring (pH meter). The two layers are separatedby decantation and the aqueous phase is extracted three times with 30 mlof CH₂Cl₂. The organic phases are joined and after drying with magnesiumsulfate, removing of the solvents under vacuo, the crude is purified byflash chromatography (CH₂Cl₂/Methanol:90/10) to yield 62, as a whitefoam.

ESI-MS: 745.2 (M+H)⁺.

Rf=0.22 (CH₂Cl₂/MeOH:94/6).

¹H-NMR (400 MHz, CD₃OD/ppm): 7.57 (s, 1H), 7.42 (A of AB, 1H), 7.32 (Bof AB, 1H), 4.74 (m, 1H), 4.34 (m, 1H), 3.80 (s, 3H), 3.75 (m, 1H), 3.22(m, 1H), 2.63 (bs, 3H), 2.45 (A of ABX, 1H), 2.18 (B of ABX, 1H), 1.81(m, 1H), 1.66 (m, 1H), 1.53-0.78 (m, 19H), 0.92 (s, 9H), 0.84 (s, 9H),0.78-0.59 (m, 3H), 0.08 (s, 3H), 0.07 (s, 6H), 0.02 (bs, 3H), −0.16 (m,1H).

(15f)—Compound 63

To a solution of 62 (160 mg) and triphenylphosphine (207 mg) in toluene(30 ml) is slowly added, at −13° C. (ice/ethanol bath) over a period ofone hour, a solution of DIAD (105 μl). The reaction is quenched byaddition of MeOH (3 ml) and the solvents are evaporated under vacuo. Thecrude mixture is then purified by flash chromatography(hexane/acetone:70/30 to 50/50 with 1% of Et₃N) to yield 63, as a whitefoam.

ESI-MS: 727.2 (M+H)⁺.

Rf=0.45 (Hex/acetone:50/50).

¹H-NMR (400 MHz, CDCl₃/ppm): 7.63 (s, 1H), 7.24 (m, 2H), 5.72 (dd, 3.7Hz, 1H), 3.99 (m, 1H), 3.89 (d, 7 Hz, 1H), 3.71 (s, 3H), 3.02 (m, 1H),2.80-2.51 (m, 2H), 2.59 (s, 3H), 2.17 (m, 1H), 1.78-0.74 (m, 9H), 1.27(s, 3H), 1.13 (s, 3H), 1.09 (d, 7 Hz, 3H), 1.0 (d, 7 Hz, 3H), 0.97 (s,9H), 0.89 (s, 9H), 0.71-0.58 (m, 3H), 0.13 (s, 6H), 0.09 (s, 3H), 0.04(s, 3H), −0.32 (m, 1H).

Example 16(1S,3S,7S,10R,11S,12S,16R)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4-oxa-bicyclo[14.1.0]heptadecane-5,9-dione(73)

To a solution of 72 (70 mg, 0.096 mmol) in 4 mL CH₃CN and in a Teflontube is added at rt 1 mL of HF.Pyridine (70/30) and the reaction mixtureis stirred 2 h at rt. The reaction mixture is washed with a 5% solutionof NaHCO₃ (pH-5), extracted 3 times with 15 mL AcOEt and then theorganic layers are dried (MgSO₄). Crude product is purified by prep-HPLCto afford pure 73 as white crystals.

ESI-MS: M(C₂₉H₄₂N₂O₅)=498.6, (M+H)⁺=499.2.

Rf: Hexane/Acetone—50/50:0.19.

¹H NMR (400 MHz, CD₃OD): δ=7.60 (s, 1H), 7.38 (m, 1H), 7.28 (m, 1H),5.97 (m, 1H), 4.30 (m, 1H), 3.92 (m, 1H), 3.70 (s, 3H), 3.30 (m, 1H),2.60 (s, 3H), 2.42 (m, 1H), 2.10 (m, 1H), 1.60 (m, 2H), 1.40 (m, 1H),1.37 (s, 3H), 1.20 (d, 3H), 1.01 (s, 3H), 0.99 (d, 3H), 0.80 (m, 1H),0.60 (m, 1H), 0.22 (m, 2H).

(16a)—Compound 65

To a solution of CrCl₂ (3.0 g, 24.06 mmol) in 10 mL THF at rt, is addeddropwise over 30 min a mixture of 57 (1.0 g, 3.0 mmol) and CH_(1S) (2.4g, 6.0 mmol) in 60 mL of Dioxane. The reaction mixture is stirred 3 h atit and quenched with 20 mL H₂O, extracted 3 times with 20 mL Et₂O and 3times with 20 mL AcOEt. The combined organic layers are dried (MgSO₄)and concentrated in vacuum. Purification by flash column chromatography(CH₂Cl₂/Acetone—100/0 to 50/50) afforded 65 in a 5/1 ratio as yellowishoil.

ESI-MS: M(C₁₉H₂₉N₂OS11)=456.4, (M+H)⁺=456.9.

Rf: Acetone—100:0.50.

¹H NMR (400 MHz, CDCl₃): S=7.58 (s, 1H), 7.20 (m, 2H), 6.52 (m, 1H),6.00 (dt, 1H), 4.80 (m, 1H), 3.70 (s, 3H), 2.80 (s, 3H), 2.40 (m, 2H),0.90 (s, 9H), 0.05 (s, 3H), −0.17 (s, 3H).

(16b)—Compound 66

To a solution of 65 (0/4 g, 1.621 mmol) in 75 mL of a CH₂Cl₂/MeOH —1/1solution, is added CSA (1.5 g, 6.485 mmol) and the reaction mixture isstirred 2 days at rt. The mixture is quenched with NaHCO₃ (5%) solutionuntil pH-7 and extracted 3 times with 25 mL AcOEt. The combined organiclayers are dried (MgSO₄) and concentrated in vacuum. Purification byflash column chromatography (CH₂Cl₂/MeOH—100/0 to 90/10) afforded 66.Crystallization in CH₂Cl₂/Hexane—1/1 with 3 drops of MeOH afforded purediastereoisomer as white crystals.

ESI-MS: M(C₁₃H₁₅N₂O₁)=342.1, (M+H)⁺=342.9.

Rf: Hexane/Acetone—50/50:0.25.

¹H NMR (400 MHz, CDCl₃): S=7.61 (s, 1H), 7.22 (m, 2H), 6.55 (m, 1H),6.15 (d, 1H), 4.85 (m, 1H), 3.73 (s, 3H), 2.61 (s, 3H), 2.55 (m, 2H).

(16c)—Compound 67

To a solution of 66 (0.28 g, 0.818 mmol) in 12 mL CH₂Cl₂ at 0° C. isadded dropwise 2,6-lutidine (0.285 mL, 2.455 mmol) followed by TESOTf(0.37 mL, 1.636 mmol). The mixture is stirred 1 h at 0° C. and then isquenched with a saturated solution of NH₄Cl, extracted 3 times with 25mL AcOEt. The combined organic layers are dried (MgSO₄) and concentratedin vacuum. Purification by flash column chromatography(Hexane/Acetone—80/20 to 50/50) afforded 67 as white crystals.

ESI-MS: M(C₁₉H₂₉N₂OSiI)=456.4, (M+H)⁺=456.9.

Rf: Hexane/Acetone—50/50:0.67.

¹H NMR (400 MHz, CDCl₃): S=7.58 (s, 1H), 7.20 (m, 2H), 6.50 (m, 1H),6.00 (dt, 1H), 4.80 (m, 1H), 3.70 (s, 3H), 2.80 (s, 3H), 2.40 (m, 2H),0.94 (t, 9H), 0.50 (q, 6H).

(16d)—Compound 68

To a 0.5M solution of 9-BBN in 4 mL THF (3.3 mL, 1.643 mmol) is addeddropwise 39 (0.417 g, 0.657 mmol) in 5 mL THF at rt. After 2 h TLCanalysis revealed the complete consumption of the starting olefin. In aseparate flask, containing 67 (0.3 g, 0.657 mmol) in 10 mL DMF wereadded successively, Cs₂CO₃ (0.428 g, 1.314 mmol), AsPh₃ (40 mg, 0.131mmol), Pd(dppf)₂Cl₂ (96 mg, 0.131 mmol) and H₂O (0.355 mL, 19.717 mmol).In first solution is added H₂O (118 μL, 6.572 mmol) to quench the excess9-BBN and the alkyl borane solution is added rapidly by syringe to thesolution containing 67. The reaction mixture is stirred 2 h at rt andquenched with H₂O, extracted 3 times with 25 mL AcOEt. The combinedorganic layers are dried (MgSO₄) and concentrated in vacuum.Purification by flash column chromatography (Hexane/Acetone—90/10 to70/30) afforded 68 as colourless oil.

ESI-MS: M(C₄₇H₈₆N₂O₆Si₃)=859.5, (M+H)⁺=859.2.

Rf: Hexane/Acetone—50/50:0.73.

¹H NMR (400 MHz, CDCl₃): S=7.60 (s, 1H), 7.20 (m, 2H), 5.40 (m, 2H),4.73 (m, 1H), 4.40 (m, 1H), 3.78 (m, 1H), 3.71 (s, 3H), 3.67 (s, 3H),3.17 (m, 1H), 2.60 (s, 3H), 2.40 (m, 2H), 2.35 (m, 2H), 1.95 (m, 2H),1.30 (m, 4H), 1.20 (s, 3H), 1.05 (s, 3H), 1.03 (d, 3H), 0.91 (d, 3H),0.90 (s, 18H), 0.90 (t, 9H), 0.50 (q, 6H), 0.12 (s, 3H), 0.05 (s, 6H),0.03 (s, 3H).

(16e)—Compound 69

To a solution of 68 (0.325 g, 0.378 mmol) in 10 mL THF at rt is added amixture TBAF/AcOH—1/1 (2.27 mL, 2.269 mmol) and the reaction is stirred5 h at rt. The solvent is removed under vacuum and the crude product ispurified by flash column chromatography (Hexane/Acetone/MeOH —50/45/5)to afford 69.

ESI-MS: M(C₄₁H₇₂N₂O₆Si₂)=745.2, (M+H)⁺=745.2.

Rf: Hexane/Acetone—50/50:0.52.

¹H NMR (400 MHz, CDCl₃): S=7.62 (s, 1H), 7.22 (m, 2H), 5.58 (m, 1H),5.41 (m, 1H), 4.80 (m, 1H), 4.40 (m, 1H), 3.78 (m, 1H), 3.71 (s, 3H),3.62 (s, 3H), 3.17 (m, 1H), 2.60 (s, 3H), 2.45 (m, 2H), 2.30 (m, 2H),2.00 (m, 2H), 1.40 (m, 4H), 1.21 (s, 3H), 1.07 (s, 3H), 1.05 (d, 3H),0.92 (d, 3H), 0.91 (s, 18H), 0.11 (s, 3H), 0.05 (s, 6H), 0.02 (s, 3H).

(16f)—Compound 70

To a 1M solution of Et₂Zn (3.38 mL, 3.38 mmol) in 5 mL CH₂Cl₂ at −13°C., is added dropwise over 10 min TFA (0.259 mL, 3.38 mmol) in 2 mLCH₂Cl₂. The reaction mixture is stirred 15 min at −13° C. and then CH₂I₂(0.273 mL, 3.38 mmol) in 2 mL CH₂Cl₂ is added dropwise. After 30 min at−13° C., 69 (0.28 g, 0.375 mmol) in 2 mL CH₂Cl₂ is added dropwise. Thereaction mixture is stirred 20 min and then is quenched with a saturatedsolution of NH₄Cl extracted 3 times with 20 mL CH₂Cl₂. The combinedorganic layers are dried (MgSO₄) and concentrated in vacuum.Purification by flash column chromatography (Hexane/Acetone—50/50)afforded 70 as colourless oil.

ESI-MS: M(C₄₂H₇₄N₂O₆Si₂)=759.2, (M+H)⁺=759.2.

Rf: Hexane/Acetone—50/50:0.28.

¹H NMR (400 MHz, CD₃OD): δ=7.58 (s, 1H), 7.42 (d, 1H), 7.30 (d, 1H),4.67 (m, 1H), 4.38 (m, 1H), 3.81 (s, 3H), 3.77 (m, 1H), 3.64 (s, 3H),3.30 (m, 1H), 3.20 (m, 1H), 2.70 (s, 3H), 2.45 (m, 1H), 2.25 (m, 1H),1.60 (m, 2H), 1.40 (m, 4H), 1.22 (s, 3H), 1.07 (s, 3H), 1.05 (d, 3H),0.92 (d, 3H), 0.91 (s, 18H), 0.32 (m, 2H), 0.15 (s, 3H), 0.08 (s, 3H),0.05 (s, 3H), 0.02 (s, 3H).

(16g)—Compound 71

To a solution of 70 (0.22 g, 0.289 mmol) in 9 mL i-PrOH/H₂O —4/1 isadded LiOH (42 mg, 1.738 mmol) and the mixture is heated 3 h at 60° C.(out). After cooling to rt, the solution is quenched with a 2% solutionof KHSO₄ (pH-5) extracted twice with 10 mL CH₂Cl₂ and twice with 10 mLAcOEt. The combined organic layers are dried (MgSO₄) and concentrated invacuum. Purification by flash column chromatography(Hexane/Acetone/MeOH—90/10/0 to 45/45/10) afforded 71 as an oil.

ESI-MS: M(C₄₁H₇₂N₂O₆Si₂)=745.2, (M+H)⁺=745.2.

Rf: Hexane/Acetone—50/50:0.23.

¹H NMR (400 MHz, CD₃OD): δ=7.58 (s, 1H), 7.42 (d, 1H), 7.30 (d, 1H),4.79 (m, 1H), 4.38 (m, 1H), 3.80 (s, 3H), 3.76 (m, 1H), 3.74 (m, 1H),3.20 (m, 1H), 2.60 (s, 3H), 2.41 (m, 1H), 2.20 (m, 1H), 1.98 (m, 2H),1.40 (m, 4H), 1.21 (s, 3H), 1.10 (s, 3H), 1.05 (d, 3H), 0.94 (d, 3H),0.94 (s, 9H), 0.93 (s, 9H), 0.28 (m, 2H), 0.10 (s, 3H), 0.07 (s, 3H),0.04 (s, 3H), 0.02 (s, 3H).

(16h) Compound 72(1S,3S,7S,10R,11S,12S,16R)-7,11-Bis-(t-butyl-dimethyl-silanyloxy)-3-(1,2-dimethyl-1H-benzoimidazol-5-yl)-8,8,10,12-tetramethyl-4-oxa-bicyclo[14.1.0]heptadecane-5,9-dione

To a solution of 71 (0.1 g, 0.134 mmol) in 25 mL toluene at −10° C. isadded PPH₃ (0.106 g, 0.402 mmol) followed by DIAD (52 μL, 0.268 mmol) in8 mL toluene dropwise over 1h30. The reaction mixture is quenched with asaturated NH₄Cl solution and extracted 3 times with 20 mL AcOEt. Thecombined organic layers are dried (MgSO₄) and concentrated in vacuum.Purification by flash column chromatography (Hexane/Acetone—50/50 to0/100) afforded 72, 70% conversion.

ESI-MS: M(C₄₁H₇₀N₂O₅S₁₂)=727.2, (M+H)⁺=727.2.

Rf: Hexane/Acetone—50/50:0.53.

¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.22 (m, 2H), 5.88 (m, 1H),4.10 (m, 1H), 3.92 (m, 1H), 3.70 (s, 3H), 3.18 (m, 1H), 2.80 (m, 2H),2.60 (s, 3H), 2.00 (m, 2H), 1.60 (m, 2H), 1.40 (m, 4H), 1.25 (s, 3H),1.24 (d, 3H), 1.15 (s, 3H), 1.13 (d, 3H), 0.98 (s, 9H), 0.84 (s, 9H),0.20 (m, 2H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), −0.05 (s, 3H).

Example 17 Proliferation Inhibition (IC50) of Epothilone Derivatives(Examples 1-16) towards KB-31 and KB-8511 Cell Lines. Method asDescribed Above

KB-31 [nmol l⁻¹] KB-8511 [nmol l⁻¹] Example 1 106.0 75.4 Example 2 5.122.18 Example 3 54.9 50.4 62.0 62.3 Example 4 6.56 36.6 7.95 39.2 7.6537.1 Example 5 2.57 2.64 5.75 5.49 Example 6 <2 <2 0.536 1.61 Example 739.1 50.2 41.9 49.9 Example 8 2.76 5.83 Example 9 3.91 10.3 4.79 13.32.07 4.37 3.7 10.5 Example 10 0.588 6.89 0.594 6.15 <2 3.25 0.596 6.83Example 11 2.57 25.1 5.17 36.6 4.63 37 Example 12 0.27 1.45 0.24 1.670.228 0.96 Example 13 144.2 74.1 137.7 68.8 152.5 73.5 Example 14 5.012.4 3.5 9.92 Example 15 0.467 1.01 Example 16 0.149 0.11

1. A compound of formula I

wherein

R₁ is R₂ is methyl or hydrogen; R₃ is hydrogen; Z is O;

is a single or double bond between C2 and C3; or salts thereof. 2-3.(canceled)
 4. The compound of formula I according to claim 1 selectedfrom the group consisting of,3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;(1S,3S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;(1S,3S,7S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;and(E)-(1S,3S,10R,11S,12S,16S)-3-(1,2-Dimethyl-1H-benzoimidazol-5-yl)-11-hydroxy-8,8,10,12-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadec-6-ene-5,9-dione.5. A pharmaceutical composition, comprising a compound of claim 1, or asalt thereof, provided that salt-forming groups are present, and one ormore pharmaceutically acceptable carriers. 6-9. (canceled)